Patent Publication Number: US-2018030452-A1

Title: Targeting oligonucleotides and uses thereof to modulate gene expression

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. U.S. 62/115,739, entitled “TARGETING OLIGONUCLEOTIDES AND USES THEREOF TO MODULATE GENE EXPRESSION”, filed on Feb. 13, 2015, the contents of which are incorporated herein by reference in its entirety. 
    
    
     FIELD OF THE INVENTION 
     The invention relates to oligonucleotide based compositions, as well as methods of using oligonucleotide based compositions for treating disease. 
     BACKGROUND OF THE INVENTION 
     Modulation of gene expression is an important tool for basic research and for treating diseases caused by defective expression (either upregulation or downregulation) of one or more genes. Obtaining specificity with respect to modulation of a target gene as well as achieving sufficient modulation (e.g., sufficient upregulation or downregulation) to obtain a desired result, e.g., treatment of disease, remains a challenge. Additionally, limited approaches are available for increasing the expression of genes. 
     SUMMARY OF THE INVENTION 
     Aspects of the invention disclosed herein provide methods and compositions that are useful for modulating (e.g., upregulating) expression of a target gene in cells. In some embodiments, single stranded oligonucleotides are provided that target a low-abundance non-coding RNA (lancRNA) of a target gene, e.g., encoding a protein of interest. In some embodiments, single stranded oligonucleotides are provided that target a lancRNA of a target gene (e.g., a human gene) and thereby cause modulation (e.g., upregulation) of the gene. In some embodiments, the target gene is a gene listed in Table 1. In some embodiments, these single stranded oligonucleotides modulate (e.g., activate or enhance) expression of a target gene by degrading the lancRNA or blocking the activity of the lancRNA. In some embodiments, these single stranded oligonucleotides modulate (e.g., activate or enhance) expression of a target gene to treat a disease or condition associated with reduced expression of the target gene. In some embodiments, the disease or condition associated with reduced expression of the target gene is listed is Table 2. 
     Further aspects of the invention provide methods for selecting oligonucleotides for modulating (e.g., activating or enhancing) expression of a target gene. In some embodiments, the target gene may be a target gene listed in Table 1, such as ABCA1, APOA1, ATP2A2, BDNF, FXN, HBA2, HBB, HBD, HBE1, HBG1, HBG2, SMN, UTRN, PTEN, MECP2, FOXP3, NFE2L2 (NRF2), THRB, NR1H4 (FXR), HAMP, ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, or PRKAG3. In some embodiments, methods are provided for selecting a set of oligonucleotides that is enriched in candidates (e.g., compared with a random selection of oligonucleotides) for modulating (e.g., activating or enhancing) expression of a target gene. Accordingly, the methods may be used to establish sets of clinical candidates that are enriched in oligonucleotides that modulate (e.g., activate or enhance) expression of a target. Such libraries may be utilized, for example, to identify lead oligonucleotides for developing therapeutics to treat a disease or condition associated with reduced or enhanced expression of the target gene. In some embodiments, the disease or condition associated with reduced expression of the target gene is listed is Table 2 or otherwise disclosed herein. Furthermore, in some embodiments, oligonucleotide chemistries are provided that are useful for controlling the pharmacokinetics, biodistribution, bioavailability and/or efficacy of the single stranded oligonucleotides for modulating (e.g., activating) expression of a target gene. 
     In some aspects, a method of modulating expression of a target gene in cells is provided, the method comprising: delivering to the cells a single-stranded oligonucleotide of 8 to 50 nucleotides in length that comprises a region of complementarity that is complementary with at least 5 contiguous nucleotides of a low-abundance non-coding RNA (lancRNA) that modulates expression of a target gene in the cells, wherein the at least 5 contiguous nucleotides of the lancRNA are transcribed from a chromosomal region within 5 kb of a transcriptional boundary of the target gene. 
     In some embodiments, the lancRNA is represented at a level of less than 0.01 fragments per kilobase per million mapped reads (FPKM) based sequencing of RNA of the cells. In some embodiments, the lancRNA is represented at an average copy number of less than 10 (e.g., less than 0.1 or less than 0.0001) transcripts per cell. In some embodiments, the average copy number of the lancRNA is less than 1% of the average copy number of transcripts expressed from the target gene in the cells. 
     In some embodiments, the lancRNA is transcribed from the same strand of the chromosomal region as the target gene. In some embodiments, the lancRNA is transcribed from the opposite strand of the chromosomal region as the target gene. 
     In some embodiments, the at least 5 contiguous nucleotides of the lancRNA are transcribed from a chromosomal region within 5 kb (e.g., within 2 kb, within 1 kb, within 500 kb or within 250 bp) of a transcriptional boundary of the target gene. 
     In some embodiments, the transcriptional boundary is a transcriptional start site. In some embodiments, the transcriptional boundary is a transcriptional end site. 
     In some embodiments, the lancRNA is no more than 200 nucleotides in length. 
     In some embodiments, the target gene is ABCA1, APOA1, ATP2A2, BDNF, FXN, HBA2, HBB, HBD, HBE1, HBG1, HBG2, SMN, UTRN, PTEN, MECP2, FOXP3, NFE2L2 (NRF2), THRB, NR1H4 (FXR), HAMP, ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, or PRKAG3. In some embodiments, the target gene is FXN. 
     In some embodiments, the oligonucleotide does not comprise three or more consecutive guanosine nucleotides. In some embodiments, the oligonucleotide does not comprise four or more consecutive guanosine nucleotides. 
     In some embodiments, the oligonucleotide is 8 to 30 nucleotides in length. In some embodiments, the oligonucleotide is 8 to 10 nucleotides in length and all but 1, 2, or 3 of the nucleotides of the complementary sequence of the lancRNA are cytosine or guanosine nucleotides. 
     In some embodiments, at least one nucleotide of the oligonucleotide is a nucleotide analogue. In some embodiments, the at least one nucleotide analogue results in an increase in Tm of the oligonucleotide in a range of 1 to 5° C. compared with an oligonucleotide that does not have the at least one nucleotide analogue. 
     In some embodiments, at least one nucleotide of the oligonucleotide comprises a 2′ O-methyl. In some embodiments, each nucleotide of the oligonucleotide comprises a 2′ O-methyl. 
     In some embodiments, wherein the oligonucleotide comprises at least one ribonucleotide, at least one deoxyribonucleotide, or at least one bridged nucleotide. In some embodiments, the bridged nucleotide is a LNA nucleotide, a cEt nucleotide or a ENA modified nucleotide. In some embodiments, each nucleotide of the oligonucleotide is a LNA nucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and 2′-fluoro-deoxyribonucleotides. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and 2′-O-methyl nucleotides. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and ENA nucleotide analogues. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and LNA nucleotides. In some embodiments, the 5′ nucleotide of the oligonucleotide is a deoxyribonucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise alternating LNA nucleotides and 2′-O-methyl nucleotides. In some embodiments, the 5′ nucleotide of the oligonucleotide is a LNA nucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise deoxyribonucleotides flanked by at least one LNA nucleotide on each of the 5′ and 3′ ends of the deoxyribonucleotides. 
     In some embodiments, the oligonucleotide further comprises phosphorothioate internucleotide linkages between at least two nucleotides. In some embodiments, the oligonucleotide further comprises phosphorothioate internucleotide linkages between all nucleotides. 
     In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ hydroxyl group. In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ thiophosphate. 
     In some embodiments, the oligonucleotide further comprises a biotin moiety conjugated to the 5′ nucleotide. 
     In some embodiments, the oligonucleotide comprises a nucleotide sequence as set for in Table 3. 
     Other aspects provide a single stranded oligonucleotide having a nucleotide sequence as set forth in Table 3. 
     In some embodiments, at least one nucleotide of the oligonucleotide comprises a 2′ O-methyl. In some embodiments, each nucleotide of the oligonucleotide comprises a 2′ O-methyl. 
     In some embodiments, the oligonucleotide comprises at least one ribonucleotide, at least one deoxyribonucleotide, or at least one bridged nucleotide. In some embodiments, the bridged nucleotide is a LNA nucleotide, a cEt nucleotide or a ENA modified nucleotide. In some embodiments, each nucleotide of the oligonucleotide is a LNA nucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and 2′-fluoro-deoxyribonucleotides. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and 2′-O-methyl nucleotides. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and ENA nucleotide analogues. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and LNA nucleotides. In some embodiments, the 5′ nucleotide of the oligonucleotide is a deoxyribonucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise alternating LNA nucleotides and 2′-O-methyl nucleotides. In some embodiments, the 5′ nucleotide of the oligonucleotide is a LNA nucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise deoxyribonucleotides flanked by at least one LNA nucleotide on each of the 5′ and 3′ ends of the deoxyribonucleotides. 
     In some embodiments, the oligonucleotide further comprises phosphorothioate internucleotide linkages between at least two nucleotides. 
     In some embodiments, the oligonucleotide further comprises phosphorothioate internucleotide linkages between all nucleotides. 
     In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ hydroxyl group. 
     In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ thiophosphate. 
     In some embodiments, the oligonucleotide further comprises a biotin moiety conjugated to the 5′ nucleotide. 
     In some embodiments, the modification pattern for the oligonucleotide is the modification pattern provided in Table 3. 
     Other aspects relate to a composition comprising a single stranded oligonucleotide as described herein, such as in any embodiment described above, and a carrier. In some embodiments, the carrier is a peptide. In some embodiments, the carrier is a steroid. In some embodiments, the oligonucleotide is conjugated to the carrier. 
     Yet other aspects relate to a composition comprising a single stranded oligonucleotide as described herein, such as in any embodiment described above, in a buffered solution. 
     In another aspect a pharmaceutical composition is provided comprising a composition as described herein, such as in any embodiment described above, and a pharmaceutically acceptable carrier. 
     In yet another aspect a kit is provided comprising a container housing a composition as described herein, such as in any embodiment described above. 
     In other aspects, a method of modulating expression of a target gene in cells is provided, the method comprising: 
     i) determining presence of a low-abundance non-coding RNA (lancRNA) in cells; and 
     ii) based on the determination made in i), delivering to the cells a single-stranded oligonucleotide of 8 to 50 nucleotides in length that comprises a region of complementarity that is complementary with at least 5 contiguous nucleotides of a lancRNA that modulates expression of a target gene in the cells, wherein the at least 5 contiguous nucleotides of the lancRNA are transcribed from a chromosomal region within 5 kb of a transcriptional boundary of the target gene. 
     In some embodiments, in step i) the lancRNA is determined to be present at a level of less than 0.01 fragments per kilobase per million mapped reads (FPKM) based sequencing of RNA of the cells. In some embodiments, in step i) the lancRNA is determined to be present at an average copy number of less than 10 (e.g., less than 0.1 or less than 0.0001) transcripts per cell. In some embodiments, in step i) the lancRNA is determined to be present at less than 1% of the average copy number of transcripts expressed from the target gene in the cells. 
     In another aspect, a method of modulating expression of a target gene in cells is provided, the method comprising: delivering to the cells a single-stranded oligonucleotide of 8 to 50 nucleotides in length that comprises a region of complementarity that is complementary with at least 5 contiguous nucleotides of a chromosomal region that corresponds to a 3′ UTR of the target gene, wherein the at least 5 contiguous nucleotides are antisense to the target gene. In some embodiments, the method comprises delivering to the cells a single-stranded oligonucleotide of 8 to 50 nucleotides in length that comprises a region of complementarity that is complementary with at least 5 contiguous nucleotides of a chromosomal region that encodes a 3′ UTR of the target gene, wherein the at least 5 contiguous nucleotides are on the opposite strand of the chromosomal region as the target gene. 
     In some embodiments, the target gene is ABCA1, APOA1, ATP2A2, BDNF, FXN, HBA2, HBB, HBD, HBE1, HBG1, HBG2, SMN, UTRN, PTEN, MECP2, FOXP3, NFE2L2 (NRF2), THRB, NR1H4 (FXR), HAMP, ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, or PRKAG3. In some embodiments, the target gene is FXN. 
     In some embodiments, the oligonucleotide does not comprise three or more consecutive guanosine nucleotides. In some embodiments, the oligonucleotide does not comprise four or more consecutive guanosine nucleotides. 
     In some embodiments, the oligonucleotide is 8 to 30 nucleotides in length. In some embodiments, the oligonucleotide is 8 to 10 nucleotides in length and all but 1, 2, or 3 of the nucleotides of the complementary sequence of the lancRNA are cytosine or guanosine nucleotides. 
     In some embodiments, at least one nucleotide of the oligonucleotide is a nucleotide analogue. In some embodiments, the at least one nucleotide analogue results in an increase in Tm of the oligonucleotide in a range of 1 to 5° C. compared with an oligonucleotide that does not have the at least one nucleotide analogue. In some embodiments, at least one nucleotide of the oligonucleotide comprises a 2′ O-methyl. In some embodiments, the oligonucleotide comprises at least one ribonucleotide, at least one deoxyribonucleotide, or at least one bridged nucleotide. In some embodiments, the bridged nucleotide is a LNA nucleotide, a cEt nucleotide or a ENA modified nucleotide. 
     In some embodiments, the oligonucleotide further comprises phosphorothioate internucleotide linkages between at least two nucleotides. In some embodiments, the oligonucleotide further comprises phosphorothioate internucleotide linkages between all nucleotides. 
     In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ hydroxyl group. In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ thiophosphate. 
     In some embodiments, a single stranded oligonucleotide provided herein comprises a fragment of at least 8 nucleotides of a nucleotide sequence as set forth in Table 3. In some embodiments, the single stranded oligonucleotide comprises or consists of a nucleotide sequence as set forth in Table 3. In some embodiments, the single stranded oligonucleotide comprises or consists of a modification pattern as set forth in Table 3. In some embodiments, one or more sequences in Table 3 are excluded, e.g., FXN-375, FXN-390, FXN-577, and FXN-578 in Table 3 are excluded. 
     In some embodiments, the single stranded oligonucleotide does not comprise three or more consecutive guanosine nucleotides. In some embodiments, the single stranded oligonucleotide does not comprise four or more consecutive guanosine nucleotides. 
     In some embodiments, the single stranded oligonucleotide is 8 to 30 nucleotides in length. In some embodiments, the single stranded oligonucleotide is up to 50 nucleotides in length. In some embodiments, the single stranded oligonucleotide is 8 to 10 nucleotides in length and all but 1, 2, or 3 of the nucleotides of the complementary sequence of the lancRNA are cytosine or guanosine nucleotides. 
     In some embodiments, the single stranded oligonucleotide is complementary with at least 8 consecutive nucleotides of a lancRNA of a target gene, in which the nucleotide sequence of the single stranded oligonucleotide comprises one or more of a nucleotide sequence selected from the group consisting of 
     (a) (X)Xxxxxx, (X)xXxxxx, (X)xxXxxx, (X)xxxXxx, (X)xxxxXx and (X)xxxxxX, 
     (b) (X)XXxxxx, (X)XxXxxx, (X)XxxXxx, (X)XxxxXx, (X)XxxxxX, (X)xXXxxx, (X)xXxXxx, (X)xXxxXx, (X)xXxxxX, (X)xxXXxx, (X)xxXxXx, (X)xxXxxX, (X)xxxXXx, (X)xxxXxX and (X)xxxxXX, 
     (c) (X)XXXxxx, (X)xXXXxx, (X)xxXXXx, (X)xxxXXX, (X)XXxXxx, (X)XXxxXx, (X)XXxxxX, (X)xXXxXx, (X)xXXxxX, (X)xxXXxX, (X)XxXXxx, (X)XxxXXx (X)XxxxXX, (X)xXxXXx, (X)xXxxXX, (X)xxXxXX, (X)xXxXxX and (X)XxXxXx, 
     (d) (X)xxXXX, (X)xXxXXX, (X)xXXxXX, (X)xXXXxX, (X)xXXXXx, (X)XxxXXXX, (X)XxXxXX, (X)XxXXxX, (X)XxXXx, (X)XXxxXX, (X)XXxXxX, (X)XXxXXx, (X)XXXxxX, (X)XXXxXx, and (X)XXXXxx, 
     (e) (X)xXXXXX, (X)XxXXXX, (X)XXxXXX, (X)XXXxXX, (X)XXXXxX and (X)XXXXXx, and 
     (f) XXXXXX, XxXXXXX, XXxXXXX, XXXxXXX, XXXXxXX, XXXXXxX and XXXXXXx, wherein “X” denotes a nucleotide analogue, (X) denotes an optional nucleotide analogue, and “x” denotes a DNA or RNA nucleotide unit. 
     In some embodiments, at least one nucleotide of the oligonucleotide is a nucleotide analogue. In some embodiments, the at least one nucleotide analogue results in an increase in Tm of the oligonucleotide in a range of 1 to 5° C. compared with an oligonucleotide that does not have the at least one nucleotide analogue. 
     In some embodiments, at least one nucleotide of the oligonucleotide comprises a 2′ O-methyl. In some embodiments, each nucleotide of the oligonucleotide comprises a 2′ O-methyl. In some embodiments, the oligonucleotide comprises at least one ribonucleotide, at least one deoxyribonucleotide, or at least one bridged nucleotide. In some embodiments, the bridged nucleotide is a LNA nucleotide, a cEt nucleotide or a ENA modified nucleotide. In some embodiments, each nucleotide of the oligonucleotide is a LNA nucleotide. 
     In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and 2′-fluoro-deoxyribonucleotides. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and 2′-O-methyl nucleotides. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and ENA nucleotide analogues. In some embodiments, the nucleotides of the oligonucleotide comprise alternating deoxyribonucleotides and LNA nucleotides. In some embodiments, the 5′ nucleotide of the oligonucleotide is a deoxyribonucleotide. In some embodiments, the nucleotides of the oligonucleotide comprise alternating LNA nucleotides and 2′-O-methyl nucleotides. In some embodiments, the 5′ nucleotide of the oligonucleotide is a LNA nucleotide. In some embodiments, the nucleotides of the oligonucleotide comprise deoxyribonucleotides flanked by at least one LNA nucleotide on each of the 5′ and 3′ ends of the deoxyribonucleotides. 
     In some embodiments, the single stranded oligonucleotide comprises modified internucleotide linkages (e.g., phosphorothioate internucleotide linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. In some embodiments, the single stranded oligonucleotide comprises modified internucleotide linkages (e.g., phosphorothioate internucleotide linkages or other linkages) between all nucleotides. 
     In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ hydroxyl group. In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ thiophosphate. In some embodiments, the single stranded oligonucleotide has a biotin moiety or other moiety conjugated to its 5′ or 3′ nucleotide. In some embodiments, the single stranded oligonucleotide has cholesterol, Vitamin A, folate, sigma receptor ligands, aptamers, peptides, such as CPP, hydrophobic molecules, such as lipids, ASGPR or dynamic polyconjugates and variants thereof at its 5′ or 3′ end. 
     According to some aspects of the invention compositions are provided that comprise any of the oligonucleotides disclosed herein, and a carrier. In some embodiments, compositions are provided that comprise any of the oligonucleotides in a buffered solution. In some embodiments, the oligonucleotide is conjugated to the carrier. In some embodiments, the carrier is a peptide. In some embodiments, the carrier is a steroid. According to some aspects of the invention pharmaceutical compositions are provided that comprise any of the oligonucleotides disclosed herein, and a pharmaceutically acceptable carrier. 
     According to other aspects of the invention, kits are provided that comprise a container housing any of the compositions disclosed herein. 
     According to some aspects of the invention, methods of modulatin (e.g., increasing) expression of a target gene in a cell are provided. In some embodiments, the methods involve delivering any one or more of the single stranded oligonucleotides disclosed herein into the cell. In some embodiments, delivery of the single stranded oligonucleotide into the cell results in a level of expression of the target gene that is greater (e.g., at least 50% greater) than a level of expression of the target gene in a control cell that does not comprise the single stranded oligonucleotide. 
     According to some aspects of the invention, methods of increasing levels of a target gene in a subject are provided. According to some aspects of the invention, methods of treating a disease or condition (e.g., a disease or condition provided in Table 2) associated with decreased levels of a target gene in a subject are provided. In some embodiments, the methods involve administering any one or more of the single stranded oligonucleotides disclosed herein to the subject. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a diagram showing the APOA1 gene locus with oligos targeting 5′/3′ antisense regions encoding lancRNAs. 
         FIG. 2A  is a diagram FXN gene locus with oligos targeting 3′ antisense regions encoding lancRNAs. 
         FIG. 2B  is a diagram FXN gene locus with oligos targeting 5′ antisense regions encoding lancRNAs. The sequences correspond to SEQ ID NO: 296. 
         FIG. 3A  is a graph showing APOA1 mRNA levels in cells treated with APOA1 oligos (oligos are those shown in Table 3, “26”=Apoa1_mus-26, “27”=Apoa1_mus-27, etc. in Table 3). 
         FIG. 3B  is a graph showing APOA1 mRNA levels in cells treated with APOA1 oligos (oligos are those shown in Table 3, “33”=Apoa1_mus-33, “34”=Apoa1_mus-34, etc. in Table 3). 
         FIG. 3C  is a graph showing APOA1 mRNA levels in cells treated with APOA1 oligos (oligos are those shown in Table 3, “40”=Apoa1_mus-40, “41”=Apoa1_mus-41, etc. in Table 3). 
         FIG. 4A  is a photograph of a Western blot showing APOA1 protein levels in cells treated with APOA1 oligos (oligos are those shown in Table 3, “26”=Apoa1_mus-26, “27”=Apoa1_mus-27, etc. in Table 3). 
         FIG. 4B  is a photograph of a Western blot showing APOA1 protein levels in cells treated with APOA1 oligos (oligos are those shown in Table 3, “33”=Apoa1_mus-33, “34”=Apoa1_mus-34, etc. in Table 3). 
         FIG. 4C  is a photograph of a Western blot showing APOA1 protein levels in cells treated with APOA1 oligos (oligos are those shown in Table 3, “40”=Apoa1_mus-40, “41”=Apoa1_mus-41, etc. in Table 3). 
         FIG. 5  is a graph showing FXN mRNA levels is Sarsero fibroblasts treated with FXN oligos (oligos are those shown in Table 3, “606”=FXN-606, “607”=FXN-607, etc. in Table 3). The oligo names on the X-axis are, from left to right, 606-653 in numerical order. 
         FIG. 6  is a graph showing FXN mRNA levels is GM03816 cells treated with FXN oligos (oligos are those shown in Table 3, “606”=FXN-606, “607”=FXN-607, etc. in Table 3). The oligo names on the X-axis are, from left to right, 606-653 in numerical order. 
         FIG. 7  is a graph showing FXN mRNA levels is GM03816 cells treated with FXN oligos (oligos are those shown in Table 3, “800”=FXN-800, “801”=FXN-801, etc. in Table 3). For each oligo on the X-axis, the concentrations are, from left to right, 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.125 nM, or water. The oligo names on the X-axis are, from left to right, 800-804 in numerical order, 800-812 in numerical order, 588, 594, 40, 823-827 in numerical order, and 816-822 in numerical order. 
         FIG. 8  is a photograph of a Western blot showing FXN protein levels in Sarsero cells treated with FXN oligos (oligos are those shown in Table 3, “606”=FXN-606, “607”=FXN-607, etc. in Table 3). 
         FIG. 9  is a photograph of a Western blot showing FXN protein levels in GM03816 cells treated with FXN oligos (oligos are those shown in Table 3, “606”=FXN-606, “607”=FXN-607, etc. in Table 3). 
         FIG. 10A  is a graph showing FXN mRNA levels is cardiomyocytes treated with FXN oligos (oligos are those shown in Table 3, “603”=FXN-603, “62”=FXN-62, etc. in Table 3). 
         FIG. 10B  is a graph showing FXN mRNA levels is cardiomyocytes treated with FXN oligos (oligos are those shown in Table 3, “634”=FXN-634, “643”=FXN-643, etc. in Table 3). 
         FIG. 10C  is a photograph of a Western blot showing FXN protein levels is cardiomyocytes treated with FXN oligos (oligos are those shown in Table 3, “603”=FXN-603, “607”=FXN-607, etc. in Table 3). 
         FIG. 11A  is a graph showing FXN mRNA levels in a liver from a mouse treated with FXN oligos (oligos are those shown in Table 3, “603”=FXN-603, “607”=FXN-607, etc. in Table 3). 
         FIG. 11B  is a graph showing FXN mRNA levels in a liver from a mouse treated with FXN oligos (oligos are those shown in Table 3, “643”=FXN-643, etc. in Table 3). 
         FIG. 11C  is a graph showing FXN total mRNA levels a mouse treated with FXN oligos (oligos are those shown in Table 3, “603”=FXN-603, “607”=FXN-607, etc. in Table 3). 
         FIG. 11D  is a graph showing FXN total mRNA levels a mouse treated with FXN oligos (oligos are those shown in Table 3, “643”=FXN-643, etc. in Table 3). 
     
    
    
     DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION 
     Aspects of the invention relate to modulation of gene expression. A considerable portion of human diseases can be treated by selectively altering protein and/or RNA levels of disease-associated transcription units (noncoding short and long RNAs, protein-coding RNAs or other regulatory coding or noncoding genomic regions). 
     Genomic regions encoding main RNA transcript units (e.g., genes) also produce RNA species such as PARs (promoter-associated RNAs) and TARs (termini-associated RNAs), which are a class of short (e.g., &lt;200 nucleotides) or long noncoding RNAs expressed at low abundance at or near the 5′ and 3′ end of genes. The gene may be a protein coding gene or a gene that encodes a noncoding RNA. The low abundance noncoding RNAs (lancRNAs) from these regions can be both in sense or antisense orientation to the main transcript being produced. As described herein, single stranded oligonucleotides were designed to be complementary to chromosomal regions encoding lancRNAs, thereby targeting the lancRNAs. It was found that gene expression was modulated after administration of these oligonucleotides to cells, resulting in many instances in upregulation of genes tested (e.g., APOA1, FXN). Without wishing to be bound by theory, it is thought that targeting these lancRNAs resulted in modulation of gene expression. Again, without wishing to be bound by theory, the regulation of parent RNA behavior through these lancRNAs can be through various mechanisms, including, but not limited to, transcriptional mechanisms, splicing mechanisms, posttranscriptional mechanisms and mechanisms affecting translation efficiency and levels. The chromosomal regions containing these lancRNAs can be +/−200 nucleotides, +/−500 nucleotides, +/−1000 nucleotides, +/−5000 nucleotides, or more, of transcriptional boundaries (e.g., 5′ and 3′ ends) of genes. As used herein, the term “low abundance noncoding RNA (lancRNA)” has its common meaning in the art and generally refers to a non-coding RNA that is present at low levels in cells, for example, at levels of less than 50 transcripts per cell. In some embodiments, a low abundance noncoding RNA has a copy number (e.g., average copy number) in a population of appropriate cells of less than 50, less than 40, less than 30, less than 20, less than 10, less than 5, less than 3, less than 1, less than 0.1, less than 0.01, less than 0.001 or less than 0.0001 transcripts per cell in the population. In some embodiments, a low abundance noncoding RNA is at a level of less than 100, less than 50, less than 40, less than 30, less than 20, less than 10, less than 1, less than 0.1, less than 0.01, less than 0.001, less than 0.0001 fragments per kilobase per million mapped reads (FPKM) based sequencing of RNA obtained from cells of an appropriate cell population. In some embodiments, a low abundance noncoding RNA is at a level of less than 100, less than 50, less than 40, less than 30, less than 20, less than 10, less than 1, less than 0.1, less than 0.01, less than 0.001, less than 0.0001 reads per kilobase per million mapped reads (RPKM) based sequencing of RNA obtained from cells of an appropriate cell population. In some embodiments, a low abundance noncoding RNA has a copy number (e.g., an average copy number) in a population of appropriate cells of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 1%, less than 0.5%, less than 0.05%, less than 0.01% or less than 0.001%, of the average copy number of transcripts expressed from a target gene of the low abundance noncoding RNA in cells of the population. Methods for calculating FPKM, RPKM, and copy number are well known in the art (see, e.g., Hart et al. Finding the active genes in deep RNA-seq gene expression studies. BMC Genomics. 2013 Nov. 11; 14:778; and Trapnell et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010 May; 28(5):511-5). 
     In some embodiments, the lancRNA has a length of no more than 1000, 500, 400, 300, or 200 nucleotides. In some embodiments, the lancRNA has a length of between 10 and 1000 nucleotides, 10 and 500 nucleotides, 10 and 400 nucleotides, 10 and 300 nucleotides, 10 and 200 nucleotides, 50 and 1000 nucleotides, 50 and 500 nucleotides, 50 and 400 nucleotides, 50 and 300 nucleotides, 50 and 200 nucleotides, 100 and 1000 nucleotides, 100 and 500 nucleotides, 100 and 400 nucleotides, 100 and 300 nucleotides, or 100 and 200 nucleotides. 
     In some embodiments, single stranded oligonucleotides are provided that specifically bind to, or are complementary to, a lancRNA transcribed from a genomic region that is within, spans or is in proximity to a target gene. In some embodiments, single stranded oligonucleotides are provided that specifically bind to, or are complementary to, a lancRNA that is transcribed from a chromosomal region that encompasses +/−100 nucleotides, +/−200 nucleotides, +/−300 nucleotides, +/−400 nucleotides, +/−500 nucleotides, +/−600 nucleotides, +/−700 nucleotides, +/−800 nucleotides, +/−900 nucleotides, +/−1000 nucleotides, +/−2000 nucleotides, +/−3000 nucleotides, +/−4000 nucleotides, +/−5000 nucleotides, or more, of a 5′ or 3′ end of a target gene. The lancRNA may be transcribed from the strand that is antisense to the target gene or sense to the target gene. 
     Accordingly, in some aspects the invention contemplates single stranded oligonucleotides that specifically bind to, or are complementary to, a sense strand or antisense strand of a chromosomal region that encompasses +/−100 nucleotides, +/−200 nucleotides, +/−300 nucleotides, +/−400 nucleotides, +/−500 nucleotides, +/−600 nucleotides, +/−700 nucleotides, +/−800 nucleotides, +/−900 nucleotides, +/−1000 nucleotides, +/−2000 nucleotides, +/−3000 nucleotides, +/−4000 nucleotides, +/−5000 nucleotides, or more, of a transcriptional boundary (e.g., a 5′ or 3′ end) of a target gene. In some embodiments, the single stranded oligonucleotide specifically binds to, or is complementary to, a region of an antisense strand (relative to the target gene) within a chromosomal region that encodes a 3′UTR of the target gene. In some embodiments, the single stranded oligonucleotide specifically binds to, or is complementary to, a region of a sense strand (relative to the target gene) within a chromosomal region that encodes a 3′UTR of the target gene. In some embodiments, the single stranded oligonucleotide specifically binds to, or is complementary to, a region of an antisense strand (relative to the target gene) within a chromosomal region that encodes a 5′UTR of the target gene. In some embodiments, the single stranded oligonucleotide specifically binds to, or is complementary to, a region of a sense strand (relative to the target gene) within a chromosomal region that encodes a 5′UTR of the target gene. 
     Methods for identifying transcript ends (e.g., transcriptional start sites and polyadenylation junctions) are known in the art and may be used in selecting oligonucleotides that specifically bind to lancRNAs transcribed from chromosomal regions encompassing these ends. In some embodiments, 3′ end oligonucleotides may be designed by identifying RNA 3′ ends (also referred to herein as transcription end sites) using quantitative end analysis of poly-A tails, designating a window (e.g., 200 nucleotides, 500 nucleotides, 1000 nucleotides, 2000 nucleotides, 5000 nucleotides, or more) that encompasses the 3′ end, and designing oligonucleotides that are complementary to either the sense or antisense strand relative to the target gene within the designated window. In some embodiments, 5′ end oligonucleotides may be designed by identifying 5′ start sites (also referred to herein as transcriptional start sites) using Cap analysis gene expression (CAGE), designating a window (e.g., 200 nucleotides, 500 nucleotides, 1000 nucleotides, 2000 nucleotides, 5000 nucleotides, or more) that encompasses the 5′ start site, and designing oligonucleotides that are complementary to either the sense or antisense strand relative to the target gene within the designated window. Appropriate methods are disclosed, for example, in Ozsolak et al. Comprehensive Polyadenylation Site Maps in Yeast and Human Reveal Pervasive Alternative Polyadenylation. Cell. Volume 143, Issue 6, 2010, Pages 1018-1029; Shiraki, T, et al., Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage. Proc Natl Acad Sci USA. 100 (26): 15776-81. 2003 Dec. 23; and Zhao, X, et al., (2011). Systematic Clustering of Transcription Start Site Landscapes. PLoS ONE (Public Library of Science) 6 (8): e23409, the contents of each of which are incorporated herein by reference. Other appropriate methods for identifying transcript start sites and polyadenylation junctions may also be used, including, for example, RNA-Paired-end tags (PET) (See, e.g., Ruan X, Ruan Y. Methods Mol Biol. 2012; 809:535-62); use of standard EST databases; RACE combined with microarray or sequencing, PAS-Seq (See, e.g., Peter J. Shepard, et al., RNA. 2011 April; 17(4): 761-772); and 3P-Seq (See, e.g., Calvin H. Jan, Nature. 2011 Jan. 6; 469(7328): 97-101; and others. 
     In some embodiments, the target gene is a gene provided in Table 1. In some embodiments, the transcriptional boundaries of the target gene refer to the 5′ and 3′ end of the exemplary mRNA provided in Table 1 for the target gene. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Non-limiting examples of RNA transcripts for certain genes 
               
            
           
           
               
               
               
               
            
               
                 GENE  
                   
                   
                   
               
               
                 SYMBOL 
                 MRNA 
                 SPECIES 
                 GENE NAME 
               
               
                   
               
               
                 ABCA1 
                 NM_013454 
                 
                   Mus  
                 
                 ATP-binding cassette, sub-family A (ABC1),  
               
               
                   
                   
                 
                   musculus 
                 
                 member 1 
               
               
                 ABCA1 
                 NM_005502 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family A (ABC1), 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 1 
               
               
                 ABCA4 
                 NM_007378 
                 
                   Mus  
                 
                 ATP-binding cassette, sub-family A (ABC1),  
               
               
                   
                   
                 
                   musculus 
                 
                 member 4 
               
               
                 ABCA4 
                 NM_000350 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family A (ABC1), 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 ABCB11 
                 NM_003742 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family B  
               
               
                   
                   
                 
                   sapiens 
                 
                 (MDR/TAP), member 11 
               
               
                 ABCB11 
                 NM_021022 
                 
                   Mus  
                 
                 ATP-binding cassette, sub-family B  
               
               
                   
                   
                 
                   musculus 
                 
                 (MDR/TAP), member 11 
               
               
                 ABCB4 
                 NM_018850 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family B  
               
               
                   
                   
                 
                   sapiens 
                 
                 (MDR/TAP), member 4 
               
               
                 ABCB4 
                 NM_000443 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family B  
               
               
                   
                   
                 
                   sapiens 
                 
                 (MDR/TAP), member 4 
               
               
                 ABCB4 
                 NM_018849 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family B  
               
               
                   
                   
                 
                   sapiens 
                 
                 (MDR/TAP), member 4 
               
               
                 ABCB4 
                 NM_008830 
                 
                   Mus  
                 
                 ATP-binding cassette, sub-family B  
               
               
                   
                   
                 
                   musculus 
                 
                 (MDR/TAP), member 4 
               
               
                 ABCG5 
                 NM_022436 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family G (WHITE), 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 5 
               
               
                 ABCG5 
                 NM_031884 
                 
                   Mus  
                 
                 ATP-binding cassette, sub-family G (WHITE),  
               
               
                   
                   
                 
                   musculus 
                 
                 member 5 
               
               
                 ABCG8 
                 NM_026180 
                 
                   Mus  
                 
                 ATP-binding cassette, sub-family G (WHITE), 
               
               
                   
                   
                 
                   musculus 
                 
                 member 8 
               
               
                 ABCG8 
                 NM_022437 
                 
                   Homo 
                 
                 ATP-binding cassette, sub-family G (WHITE),  
               
               
                   
                   
                 
                   sapiens 
                 
                 member 8 
               
               
                 ADIPOQ 
                 NM_009605 
                 
                   Mus  
                 
                 adiponectin, C1Q and collagen domain 
               
               
                   
                   
                 
                   musculus 
                 
                 containing 
               
               
                 ADIPOQ 
                 NM_004797 
                 
                   Homo 
                 
                 adiponectin, C1Q and collagen domain 
               
               
                   
                   
                 
                   sapiens 
                 
                 containing 
               
               
                 ALB 
                 NM_000477 
                 
                   Homo 
                 
                 albumin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 ALB 
                 NM_009654 
                 
                   Mus  
                 
                 albumin 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 APOA1 
                 NM_000039 
                 
                   Homo 
                 
                 apolipoprotein A-I 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 APOA1 
                 NM_009692 
                 
                   Mus  
                 
                 apolipoprotein A-l 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 APOE 
                 NM_009696 
                 
                   Mus  
                 
                 apolipoprotein E 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 APOE 
                 XM_001724655 
                 
                   Homo 
                 
                 hypothetical LOC100129500;  
               
               
                   
                   
                 
                   sapiens 
                 
                 apolipoprotein E 
               
               
                 APOE 
                 XM_001722911 
                 
                   Homo 
                 
                 hypothetical LOC100129500;  
               
               
                   
                   
                 
                   sapiens 
                 
                 apolipoprotein E 
               
               
                 APOE 
                 XM_001724653 
                 
                   Homo 
                 
                 hypothetical LOC100129500;  
               
               
                   
                   
                 
                   sapiens 
                 
                 apolipoprotein E 
               
               
                 APOE 
                 NM_000041 
                 
                   Homo 
                 
                 hypothetical LOC100129500;  
               
               
                   
                   
                 
                   sapiens 
                 
                 apolipoprotein E 
               
               
                 APOE 
                 XM_001722946 
                 
                   Homo 
                 
                 hypothetical LOC100129500;  
               
               
                   
                   
                 
                   sapiens 
                 
                 apolipoprotein E 
               
               
                 ATP2A2 
                 NM_009722 
                 
                   Mus  
                 
                 ATPase, Ca++ transporting, cardiac muscle,  
               
               
                   
                   
                 
                   musculus 
                 
                 slow twitch 2 
               
               
                 ATP2A2 
                 NM_001110140 
                 
                   Mus  
                 
                 ATPase, Ca++ transporting, cardiac muscle,  
               
               
                   
                   
                 
                   musculus 
                 
                 slow twitch 2 
               
               
                 ATP2A2 
                 NM_001135765 
                 
                   Homo 
                 
                 ATPase, Ca++ transporting, cardiac muscle, 
               
               
                   
                   
                 
                   sapiens 
                 
                 slow twitch 2 
               
               
                 ATP2A2 
                 NM_170665 
                 
                   Homo 
                 
                 ATPase, Ca++ transporting, cardiac muscle,  
               
               
                   
                   
                 
                   sapiens 
                 
                 slow twitch 2 
               
               
                 ATP2A2 
                 NM_001681 
                 
                   Homo 
                 
                 ATPase, Ca++ transporting, cardiac muscle,  
               
               
                   
                   
                 
                   sapiens 
                 
                 slow twitch 2 
               
               
                 BCL2L11 
                 NM_006538 
                 
                   Homo 
                 
                 BCL2-like 11 (apoptosis facilitator) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BCL2L11 
                 NM_207002 
                 
                   Homo 
                 
                 BCL2-like 11 (apoptosis facilitator) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BCL2L11 
                 NM_138621 
                 
                   Homo 
                 
                 BCL2-like 11 (apoptosis facilitator) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BCL2L11 
                 NM_207680 
                 
                   Mus  
                 
                 BCL2-like 11 (apoptosis facilitator) 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BCL2L11 
                 NM_207681 
                 
                   Mus  
                 
                 BCL2-like 11 (apoptosis facilitator) 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BCL2L11 
                 NM_009754 
                 
                   Mus  
                 
                 BCL2-like 11 (apoptosis facilitator) 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BDNF 
                 NM_001143816 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143815 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143814 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143813 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143812 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143806 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143811 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143805 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143810 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001709 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_170735 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_170734 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_170733 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_170732 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_170731 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143809 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143807 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_001143808 
                 
                   Homo 
                 
                 brain-derived neurotrophic factor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BDNF 
                 NM_007540 
                 
                   Mus  
                 
                 brain derived neurotrophic factor 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BDNF 
                 NM_001048141 
                 
                   Mus  
                 
                 brain derived neurotrophic factor 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BDNF 
                 NM_001048142 
                 
                   Mus  
                 
                 brain derived neurotrophic factor 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BDNF 
                 NM_001048139 
                 
                   Mus  
                 
                 brain derived neurotrophic factor 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BRCA1 
                 NM_009764 
                 
                   Mus  
                 
                 breast cancer 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 BRCA1 
                 NM_007296 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007300 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007297 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007303 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007298 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007302 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007299 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007304 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007294 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007305 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 BRCA1 
                 NM_007295 
                 
                   Homo 
                 
                 breast cancer 1, early onset 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 CD274 
                 NM_014143 
                 
                   Homo 
                 
                 CD274 molecule 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 CD274 
                 NM_021893 
                 
                   Mus  
                 
                 CD274 antigen 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 CEP290 
                 NM_025114 
                 
                   Homo 
                 
                 centrosomal protein 290 kDa 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 CEP290 
                 NM_146009 
                 
                   Mus  
                 
                 centrosomal protein 290 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 CFTR 
                 NM_000492 
                 
                   Homo 
                 
                 cystic fibrosis transmembrane conductance  
               
               
                   
                   
                 
                   sapiens 
                 
                 regulator (ATP-binding cassette sub-family C,  
               
               
                   
                   
                   
                 member 7) 
               
               
                 CFTR 
                 NM_021050 
                 
                   Mus  
                 
                 cystic fibrosis transmembrane conductance 
               
               
                   
                   
                 
                   musculus 
                 
                 regulator homolog 
               
               
                 EPO 
                 NM_000799 
                 
                   Homo 
                 
                 erythropoietin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 EPO 
                 NM_007942 
                 
                   Mus  
                 
                 erythropoietin 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 F7 
                 NM_000131 
                 
                   Homo 
                 
                 coagulation factor VII (serum prothrombin 
               
               
                   
                   
                 
                   sapiens 
                 
                 conversion accelerator) 
               
               
                 F7 
                 NM_019616 
                 
                   Homo 
                 
                 coagulation factor VII (serum prothrombin  
               
               
                   
                   
                 
                   sapiens 
                 
                 conversion accelerator) 
               
               
                 F7 
                 NM_010172 
                 
                   Mus  
                 
                 coagulation factor VII 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 F8 
                 NM_019863 
                 
                   Homo 
                 
                 coagulation factor VIII, procoagulant  
               
               
                   
                   
                 
                   sapiens 
                 
                 component 
               
               
                 F8 
                 NM_000132 
                 
                   Homo 
                 
                 coagulation factor VIII, procoagulant 
               
               
                   
                   
                 
                   sapiens 
                 
                 component 
               
               
                 F8 
                 NM_001161373 
                 
                   Mus  
                 
                 coagulation factor VIII 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 F8 
                 NM_001161374 
                 
                   Mus  
                 
                 coagulation factor VIII 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 F8 
                 NM_007977 
                 
                   Mus  
                 
                 coagulation factor VIII 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 FLI1 
                 NM_002017 
                 
                   Homo 
                 
                 Friend leukemia virus integration 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FLI1 
                 NM_001167681 
                 
                   Homo 
                 
                 Friend leukemia virus integration 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FLI1 
                 NM_008026 
                 
                   Mus  
                 
                 Friend leukemia integration 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 FMR1 
                 NM_008031 
                 
                   Mus  
                 
                 fragile X mental retardation syndrome 1  
               
               
                   
                   
                 
                   musculus 
                 
                 homolog 
               
               
                 FMR1 
                 NM_002024 
                 
                   Homo 
                 
                 fragile X mental retardation 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FNDC5 
                 NM_001171941 
                 
                   Homo 
                 
                 fibronectin type III domain containing 5 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FNDC5 
                 NM_153756 
                 
                   Homo 
                 
                 fibronectin type III domain containing 5 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FNDC5 
                 NM_001171940 
                 
                   Homo 
                 
                 fibronectin type III domain containing 5 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FNDC5 
                 NM_027402 
                 
                   Mus  
                 
                 fibronectin type III domain containing 5 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 FOXP3 
                 NM_054039 
                 
                   Mus  
                 
                 forkhead box P3 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 FOXP3 
                 NM_001114377 
                 
                   Homo 
                 
                 forkhead box P3 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FOXP3 
                 NM_014009 
                 
                   Homo 
                 
                 forkhead box P3 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FXN 
                 NM_001161706 
                 
                   Homo 
                 
                 frataxin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FXN 
                 NM_181425 
                 
                   Homo 
                 
                 frataxin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FXN 
                 NM_000144 
                 
                   Homo 
                 
                 frataxin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 FXN 
                 NM_008044 
                 
                   Mus  
                 
                 frataxin 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 GCH1 
                 NM_008102 
                 
                   Mus  
                 
                 GTP cyclohydrolase 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 GCH1 
                 NM_000161 
                 
                   Homo 
                 
                 GTP cyclohydrolase 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GCH1 
                 NM_001024070 
                 
                   Homo 
                 
                 GTP cyclohydrolase 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GCH1 
                 NM_001024071 
                 
                   Homo 
                 
                 GTP cyclohydrolase 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GCH1 
                 NM_001024024 
                 
                   Homo 
                 
                 GTP cyclohydrolase 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GCK 
                 NM_010292 
                 
                   Mus  
                 
                 glucokinase 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 GCK 
                 NM_000162 
                 
                   Homo 
                 
                 glucokinase (hexokinase 4) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GCK 
                 NM_033508 
                 
                   Homo 
                 
                 glucokinase (hexokinase 4) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GCK 
                 NM_033507 
                 
                   Homo 
                 
                 glucokinase (hexokinase 4) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GLP1R 
                 NM_021332 
                 
                   Mus  
                 
                 glucagon-like peptide 1 receptor; similar to 
               
               
                   
                   
                 
                   musculus 
                 
                 glucagon-like peptide-1 receptor 
               
               
                 GLP1R 
                 XM_001471951 
                 
                   Mus  
                 
                 glucagon-like peptide 1 receptor; similar to 
               
               
                   
                   
                 
                   musculus 
                 
                 glucagon-like peptide-1 receptor 
               
               
                 GLP1R 
                 NM_002062 
                 
                   Homo 
                 
                 glucagon-like peptide 1 receptor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GRN 
                 NM_002087 
                 
                   Homo 
                 
                 granulin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 GRN 
                 NM_008175 
                 
                   Mus  
                 
                 granulin 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HAMP 
                 NM_021175 
                 
                   Homo 
                 
                 hepcidin antimicrobial peptide 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HAMP 
                 NM_032541 
                 
                   Mus  
                 
                 hepcidin antimicrobial peptide 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBA2 
                 NM_000517 
                 
                   Homo 
                 
                 hemoglobin, alpha 2; hemoglobin, alpha 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HBA2 
                 NM_000558 
                 
                   Homo 
                 
                 hemoglobin, alpha 2; hemoglobin, alpha 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HBB 
                 NM_000518 
                 
                   Homo 
                 
                 hemoglobin, beta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HBB 
                 XM_921413 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_903245 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_921395 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_903244 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_903246 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_909723 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_921422 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_489729 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_903242 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_903243 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBB 
                 XM_921400 
                 
                   Mus  
                 
                 hemoglobin beta chain complex 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HBD 
                 NM_000519 
                 
                   Homo 
                 
                 hemoglobin, delta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HBE1 
                 NM_005330 
                 
                   Homo 
                 
                 hemoglobin, epsilon 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HBG1 
                 NM_000559 
                 
                   Homo 
                 
                 hemoglobin, gamma A 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HBG2 
                 NM_000184 
                 
                   Homo 
                 
                 hemoglobin, gamma G 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HPRT1 
                 NM_000194 
                 
                   Homo 
                 
                 hypoxanthine phosphoribosyltransferase 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 IDO1 
                 NM_008324 
                 
                   Mus  
                 
                 indoleamine 2,3-dioxygenase 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IDO1 
                 NM_002164 
                 
                   Homo 
                 
                 indoleamine 2,3-dioxygenase 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 IGF1 
                 NM_001111284 
                 
                   Homo 
                 
                 insulin-like growth factor 1 (somatomedin C) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 IGF1 
                 NM_001111285 
                 
                   Homo 
                 
                 insulin-like growth factor 1 (somatomedin C) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 IGF1 
                 NM_001111283 
                 
                   Homo 
                 
                 insulin-like growth factor 1 (somatomedin C) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 IGF1 
                 NM_000618 
                 
                   Homo 
                 
                 insulin-like growth factor 1 (somatomedin C) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 IGF1 
                 NM_001111274 
                 
                   Mus  
                 
                 insulin-like growth factor 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IGF1 
                 NM_010512 
                 
                   Mus  
                 
                 insulin-like growth factor 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IGF1 
                 NM_184052 
                 
                   Mus  
                 
                 insulin-like growth factor 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IGF1 
                 NM_001111276 
                 
                   Mus  
                 
                 insulin-like growth factor 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IGF1 
                 NM_001111275 
                 
                   Mus  
                 
                 insulin-like growth factor 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IL10 
                 NM_000572 
                 
                   Mus  
                 
                 interleukin 10 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IL10 
                 NM_010548 
                 
                   Mus  
                 
                 interleukin 10 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IL6 
                 NM_031168 
                 
                   Mus  
                 
                 interleukin 6 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 IL6 
                 NM_000600 
                 
                   Homo 
                 
                 interleukin 6 (interferon, beta 2) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 KCNMA1 
                 NM_002247 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, alpha  
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMA1 
                 NM_001161352 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, alpha 
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMA1 
                 NM_001014797 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, alpha 
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMA1 
                 NM_001161353 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, alpha 
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMA1 
                 NM_010610 
                 
                   Mus  
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   musculus 
                 
                 activated channel, subfamily M, alpha 
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMB1 
                 NM_031169 
                 
                   Mus  
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   musculus 
                 
                 activated channel, subfamily M, beta 
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMB1 
                 NM_004137 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, beta  
               
               
                   
                   
                   
                 member 1 
               
               
                 KCNMB2 
                 NM_028231 
                 
                   Mus  
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   musculus 
                 
                 activated channel, subfamily M, beta 
               
               
                   
                   
                   
                 member 2 
               
               
                 KCNMB2 
                 NM_005832 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, beta 
               
               
                   
                   
                   
                 member 2 
               
               
                 KCNMB2 
                 NM_181361 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, beta  
               
               
                   
                   
                   
                 member 2 
               
               
                 KCNMB3 
                 NM_171829 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M beta 
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB3 
                 NM_171828 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M beta  
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB3 
                 NM_001163677 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M beta 
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB3 
                 NM_014407 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M beta 
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB3 
                 NM_171830 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M beta 
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB3 
                 XM_001475546 
                 
                   Mus  
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   musculus 
                 
                 activated channel, subfamily M, beta  
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB3 
                 XM_912348 
                 
                   Mus  
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   musculus 
                 
                 activated channel, subfamily M, beta  
               
               
                   
                   
                   
                 member 3 
               
               
                 KCNMB4 
                 NM_021452 
                 
                   Mus  
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   musculus 
                 
                 activated channel, subfamily M, beta  
               
               
                   
                   
                   
                 member 4 
               
               
                 KCNMB4 
                 NM_014505 
                 
                   Homo 
                 
                 potassium large conductance calcium- 
               
               
                   
                   
                 
                   sapiens 
                 
                 activated channel, subfamily M, beta  
               
               
                   
                   
                   
                 member 4 
               
               
                 KLF1 
                 NM_010635 
                 
                   Mus  
                 
                 Kruppel-like factor 1 (erythroid) 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 KLF1 
                 NM_006563 
                 
                   Homo 
                 
                 Kruppel-like factor 1 (erythroid) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 KLF4 
                 NM_010637 
                 
                   Mus  
                 
                 Kruppel-Iike factor 4 (gut) 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 KLF4 
                 NM_004235 
                 
                   Homo 
                 
                 Kruppel-like factor 4 (gut) 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 LAMA1 
                 NM_005559.3 
                 
                   Homo 
                 
                 laminin, alpha 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 LAMA1 
                 NM_008480.2 
                 
                   Mus  
                 
                 laminin, alpha 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 LDLR 
                 NM_000527 
                 
                   Homo 
                 
                 low density lipoprotein receptor 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 LDLR 
                 NM_010700 
                 
                   Mus  
                 
                 low density lipoprotein receptor 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 MBNL1 
                 NM_021038.3, 
                 
                   Homo 
                 
                 muscleblind-like splicing regulator 1 
               
               
                   
                 NM_020007.3,  
                 
                   sapiens 
                 
                   
               
               
                   
                 NM_207293.1, 
                   
                   
               
               
                   
                 NM_207294.1,  
                   
                   
               
               
                   
                 NM_207295.1, 
                   
                   
               
               
                   
                 NM_207296.1,  
                   
                   
               
               
                   
                 NM_207297.1 
                   
                   
               
               
                 MBNL1 
                 NM_001253708.1,  
                 
                   Mus  
                 
                 muscleblind-like 1 ( Drosophila ) 
               
               
                   
                 NM_001253709.1,  
                 
                   musculus 
                 
                   
               
               
                   
                 NM_001253710.1, 
                   
                   
               
               
                   
                 NM_001253711.1,  
                   
                   
               
               
                   
                 NM_001253713.1,  
                   
                   
               
               
                   
                 NM_020007.3 
                   
                   
               
               
                 MECP2 
                 NM_010788 
                 
                   Mus  
                 
                 methyl CpG binding protein 2 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 MECP2 
                 NM_001081979 
                 
                   Mus  
                 
                 methyl CpG binding protein 2 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 MECP2 
                 NM_001110792 
                 
                   Homo 
                 
                 methyl CpG binding protein 2 
               
               
                   
                   
                 
                   sapiens 
                 
                 (Rett syndrome) 
               
               
                 MECP2 
                 NM_004992 
                 
                   Homo 
                 
                 methyl CpG binding protein 2 
               
               
                   
                   
                 
                   sapiens 
                 
                 (Rett syndrome) 
               
               
                 MERTK 
                 NM_006343.2 
                 
                   Homo 
                 
                 MER proto-oncogene, tyrosine kinase 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 MERTK 
                 NM_008587.1 
                 
                   Mus  
                 
                 c-mer proto-oncogene tyrosine kinase 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 MSX2 
                 NM_013601 
                 
                   Mus  
                 
                 similar to homeobox protein; homeobox,  
               
               
                   
                   
                 
                   musculus 
                 
                 msh-like 2 
               
               
                 MSX2 
                 XM_001475886 
                 
                   Mus  
                 
                 similar to homeobox protein; homeobox, 
               
               
                   
                   
                 
                   musculus 
                 
                 msh-like 2 
               
               
                 MSX2 
                 NM_002449 
                 
                   Homo 
                 
                 msh homeobox 2 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 MYBPC3 
                 NM_008653 
                 
                   Mus  
                 
                 myosin binding protein C, cardiac 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 MYBPC3 
                 NM_000256 
                 
                   Homo 
                 
                 myosin binding protein C, cardiac 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NANOG 
                 NM_024865 
                 
                   Homo 
                 
                 Nanog homeobox pseudogene 8; Nanog 
               
               
                   
                   
                 
                   sapiens 
                 
                 homeobox 
               
               
                 NANOG 
                 XM_001471588 
                 
                   Mus  
                 
                 similar to Nanog homeobox; Nanog 
               
               
                   
                   
                 
                   musculus 
                 
                 homeobox 
               
               
                 NANOG 
                 NM_028016 
                 
                   Mus  
                 
                 similar to Nanog homeobox; Nanog 
               
               
                   
                   
                 
                   musculus 
                 
                 homeobox 
               
               
                 NANOG 
                 NM_001080945 
                 
                   Mus  
                 
                 similar to Nanog homeobox; Nanog 
               
               
                   
                   
                 
                   musculus 
                 
                 homeobox 
               
               
                 NF1 
                 NM_000267 
                 
                   Homo 
                 
                 neurofibromin 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NF1 
                 NM_001042492 
                 
                   Homo 
                 
                 neurofibromin 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NF1 
                 NM_001128147 
                 
                   Homo 
                 
                 neurofibromin 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NF1 
                 NM_010897 
                 
                   Mus  
                 
                 neurofibromatosis 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 NKX2-1 
                 NM_001079668 
                 
                   Homo 
                 
                 NK2 homeobox 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NKX2-1 
                 NM_003317 
                 
                   Homo 
                 
                 NK2 homeobox 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NKX2-1 
                 XM_002344771 
                 
                   Homo 
                 
                 KK2 homeobox 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 NKX2-1 
                 NM_009385 
                 
                   Mus  
                 
                 KK2 homeobox 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 NKX2-1 
                 NM_001146198 
                 
                   Mus  
                 
                 NK2 homeobox 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 PAH 
                 NM_008777 
                 
                   Mus  
                 
                 phenylalanine hydroxylase 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 PAH 
                 NM_000277 
                 
                   Homo 
                 
                 phenylalanine hydroxylase 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 PTEN 
                 NM_000314 
                 
                   Homo 
                 
                 phosphatase and tensin homolog;  
               
               
                   
                   
                 
                   sapiens 
                 
                 phosphatase and tensin homolog  
               
               
                   
                   
                   
                 pseudogene 1 
               
               
                 PTEN 
                 NM_177096 
                 
                   Mus  
                 
                 phosphatase and tensin homolog 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 PTEN 
                 NM_008960 
                 
                   Mus  
                 
                 phosphatase and tensin homolog 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 PTGS2 
                 NM_011198 
                 
                   Mus  
                 
                 prostaglandin-endoperoxide synthase 2 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 PTGS2 
                 NM_000963 
                 
                   Homo 
                 
                 prostaglandin-endoperoxide synthase 2  
               
               
                   
                   
                 
                   sapiens 
                 
                 (prostaglandin G/H synthase and  
               
               
                   
                   
                   
                 cyclooxygenase) 
               
               
                 RB1 
                 NM_009029 
                 
                   Mus  
                 
                 retinoblastoma 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 RB1 
                 NM_000321 
                 
                   Homo 
                 
                 retinoblastoma 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 RPS14 
                 NM_020600 
                 
                   Mus  
                 
                 predicted gene 6204; ribosomal protein S14 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 RPS14 
                 NM_001025071 
                 
                   Homo 
                 
                 ribosomal protein S14 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 RPS14 
                 NM_005617 
                 
                   Homo 
                 
                 ribosomal protein S14 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 RPS14 
                 NM_001025070 
                 
                   Homo 
                 
                 ribosomal protein S14 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 RPS19 
                 XM_204069 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19; 
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143; 
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19; 
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636; 
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_991053 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143; 
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636;  
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_905004 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683; 
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19; 
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143;  
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636; 
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_001005575 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143;  
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636;  
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 NM_023133 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19; 
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143;  
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19; 
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636; 
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_994263 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683; 
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143;  
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636; 
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_001481027 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143;  
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636; 
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_913504 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143; 
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636;  
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_001479631 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683; 
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143;  
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636;  
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_902221 
                 
                   Mus  
                 
                 predicted gene 4327; predicted gene 8683;  
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143; 
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein S19; 
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636; 
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 XM_893968 
                 Mus 
                 predicted gene 4327; predicted gene 8683; 
               
               
                   
                   
                 
                   musculus 
                 
                 similar to 40S ribosomal protein S19;  
               
               
                   
                   
                   
                 predicted gene 4510; predicted gene 13143; 
               
               
                   
                   
                   
                 predicted gene 9646; ribosomal protein 519;  
               
               
                   
                   
                   
                 predicted gene 9091; predicted gene 6636;  
               
               
                   
                   
                   
                 predicted gene 14072 
               
               
                 RPS19 
                 NM_001022 
                 
                   Homo 
                 
                 ribosomal protein S19 pseudogene 3; 
               
               
                   
                   
                 
                   sapiens 
                 
                 ribosomal protein S19 
               
               
                 SCARB1 
                 NM_016741 
                 
                   Mus  
                 
                 scavenger receptor class B, member 1 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 SCARB1 
                 NM_001082959 
                 
                   Homo 
                 
                 scavenger receptor class B, member 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 SCARB1 
                 NM_005505 
                 
                   Homo 
                 
                 scavenger receptor class B, member 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 SERPINF1 
                 NM_011340 
                 
                   Mus  
                 
                 serine (or cysteine) peptidase inhibitor,  
               
               
                   
                   
                 
                   musculus 
                 
                 clade F, member 1 
               
               
                 SERPINF1 
                 NM_002615 
                 
                   Homo 
                 
                 serpin peptidase inhibitor, clade F (alpha-2 
               
               
                   
                   
                 
                   sapiens 
                 
                 antiplasmin, pigment epithelium derived 
               
               
                   
                   
                   
                 factor), member 1 
               
               
                 SIRT1 
                 NM_001159590 
                 
                   Mus  
                 
                 sirtuin 1 (silent mating type information 
               
               
                   
                   
                 
                   musculus 
                 
                 regulation 2, homolog) 1 ( S. cerevisiae ) 
               
               
                 SIRT1 
                 NM_019812 
                 
                   Mus  
                 
                 sirtuin 1 (silent mating type information 
               
               
                   
                   
                 
                   musculus 
                 
                 regulation 2, homolog) 1 ( S. cerevisiae ) 
               
               
                 SIRT1 
                 NM_001159589 
                 
                   Mus  
                 
                 sirtuin 1 (silent mating type information 
               
               
                   
                   
                 
                   musculus 
                 
                 regulation 2, homolog) 1 ( S. cerevisiae ) 
               
               
                 SIRT1 
                 NM_012238 
                 
                   Homo 
                 
                 sirtuin (silent mating type information 
               
               
                   
                   
                 
                   sapiens 
                 
                 regulation 2 homolog) 1 ( S. cerevisiae ) 
               
               
                 SIRT1 
                 NM_001142498 
                 
                   Homo 
                 
                 sirtuin (silent mating type information 
               
               
                   
                   
                 
                   sapiens 
                 
                 regulation 2 homolog) 1 ( S. cerevisiae ) 
               
               
                 SIRT6 
                 NM_016539 
                 
                   Homo 
                 
                 sirtuin (silent mating type information 
               
               
                   
                   
                 
                   sapiens 
                 
                 regulation 2 homolog) 6 ( S. cerevisiae ) 
               
               
                 SIRT6 
                 NM_001163430 
                 
                   Mus  
                 
                 sirtuin 6 (silent mating type information 
               
               
                   
                   
                 
                   musculus 
                 
                 regulation 2, homolog) 6 ( S. cerevisiae ) 
               
               
                 SIRT6 
                 NM_181586 
                 
                   Mus  
                 
                 sirtuin 6 (silent mating type information 
               
               
                   
                   
                 
                   musculus 
                 
                 regulation 2, homolog) 6 ( S. cerevisiae ) 
               
               
                 SMAD7 
                 NM_005904 
                 
                   Homo 
                 
                 SMAD family member 7 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 SMAD7 
                 NM_001042660 
                 
                   Mus  
                 
                 MAD homolog 7 ( Drosophila ) 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 SMN1 
                 NM_000344.3 
                 
                   Homo 
                 
                 Survival Motor Neuron 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 SMN1 
                 NM_022874.2 
                 
                   Homo 
                 
                 Survival Motor Neuron 1 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 SMN2 
                 NM_017411.3  
                 
                   Homo 
                 
                 Survival Motor Neuron 2 
               
               
                   
                 NM_022875.2 
                 
                   sapiens 
                 
                   
               
               
                   
                 NM_022876.2 
                   
                   
               
               
                   
                 NM_022877.2 
                   
                   
               
               
                 SSPN 
                 NM_001135823.1,  
                 
                   Homo 
                 
                 sarcospan 
               
               
                   
                 NM_005086.4 
                 
                   sapiens 
                 
                   
               
               
                 SSPN 
                 NM_010656.2 
                 
                   Homo 
                 
                 sarcospan 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 ST7 
                 NM_021908 
                 
                   Homo 
                 
                 suppression of tumorigenicity 7 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 ST7 
                 NM_018412 
                 
                   Homo 
                 
                 suppression of tumorigenicity 7 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 STAT3 
                 NM_213660 
                 
                   Mus  
                 
                 similar to Stat3B; signal transducer and 
               
               
                   
                   
                 
                   musculus 
                 
                 activator of transcription 3 
               
               
                 STAT3 
                 XM_001474017 
                 
                   Mus  
                 
                 similar to Stat3B; signal transducer and  
               
               
                   
                   
                 
                   musculus 
                 
                 activator of transcription 3 
               
               
                 STAT3 
                 NM_213659 
                 
                   Mus  
                 
                 similar to Stat3B; signal transducer and 
               
               
                   
                   
                 
                   musculus 
                 
                 activator of transcription 3 
               
               
                 STAT3 
                 NM_011486 
                 
                   Mus  
                 
                 similar to Stat3B; signal transducer and 
               
               
                   
                   
                 
                   musculus 
                 
                 activator of transcription 3 
               
               
                 STAT3 
                 NM_213662 
                 
                   Homo 
                 
                 signal transducer and activator of 
               
               
                   
                   
                 
                   sapiens 
                 
                 transcription 3 (acute-phase response factor) 
               
               
                 STAT3 
                 NM_003150 
                 
                   Homo 
                 
                 signal transducer and activator of  
               
               
                   
                   
                 
                   sapiens 
                 
                 transcription 3 (acute-phase response factor) 
               
               
                 STAT3 
                 NM_139276 
                 
                   Homo 
                 
                 signal transducer and activator of 
               
               
                   
                   
                 
                   sapiens 
                 
                 transcription 3 (acute-phase response factor) 
               
               
                 UTRN 
                 NM_007124 
                 
                   Homo 
                 
                 utrophin 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 UTRN 
                 NM_011682 
                 
                   Mus  
                 
                 utrophin 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 NFE2L2 
                 NM_001145412.2, 
                 
                   Homo 
                 
                 nuclear factor, erythroid 2-like 2 
               
               
                   
                 NM_001145413.2,  
                 
                   sapiens 
                 
                   
               
               
                   
                 NM_006164.4 
                   
                   
               
               
                 NFE2L2 
                 NM_010902.3 
                 
                   Mus  
                 
                 nuclear factor, erythroid 2-like 2 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 ACTB 
                 NM_001101.3 
                 
                   Homo 
                 
                 actin, beta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 ACTB 
                 NM_007393.3 
                 
                   Mus  
                 
                 actin, beta 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 ANRIL 
                 NR_003529.3, 
                 
                   Homo 
                 
                 CDKN2B antisense RNA 1 
               
               
                   
                 NR_047532.1,  
                 
                   sapiens 
                 
                 (also called CDKN2B) 
               
               
                   
                 NR_047533.1,  
                   
                   
               
               
                   
                 NR_047534.1, 
                   
                   
               
               
                   
                 NR_047535.1,  
                   
                   
               
               
                   
                 NR_047536.1, 
                   
                   
               
               
                   
                 NR_047538.1, 
                   
                   
               
               
                   
                 NR_047539.1, 
                   
                   
               
               
                   
                 NR_047540.1,  
                   
                   
               
               
                   
                 NR_047541.1,  
                   
                   
               
               
                   
                 NR_047542.1, 
                   
                   
               
               
                   
                 NR 047543.1 
                   
                   
               
               
                 HOTAIR 
                 NR_003716.3,  
                 
                   Homo 
                 
                 HOX transcript antisense RNA 
               
               
                   
                 NR_047517.1, 
                 
                   sapiens 
                 
                   
               
               
                   
                 NR_047518.1 
                   
                   
               
               
                 HOT AIR 
                 NR_047528.1 
                 
                   Mus  
                 
                 HOX transcript antisense RNA 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 DINO 
                 JX993265 
                 
                   Homo 
                 
                 Damage Induced NOncoding 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 DINO 
                 JX993266 
                 
                   Mus  
                 
                 Damage Induced NOncoding 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 HOTTIP 
                 NR_037843.3 
                 
                   Homo 
                 
                 HOXA distal transcript antisense RNA 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 HOTTIP 
                 NR_110441.1,  
                 
                   Mus  
                 
                 Hoxa distal transcript antisense RNA 
               
               
                   
                 NR 110442.1 
                 
                   musculus 
                 
                   
               
               
                 NEST 
                 NR_104124.1 
                 
                   Homo 
                 
                   Homo   sapiens  IFNG antisense RNA 1  
               
               
                   
                   
                 
                   sapiens 
                 
                 (IFNG-AS1), transcript variant 1, long 
               
               
                   
                   
                   
                 non-coding RNA. 
               
               
                 NEST 
                 NR_104123.1 
                 
                   Mus  
                 
                 Theiler&#39;s murine encephalomyelitis virus  
               
               
                   
                   
                 
                   musculus 
                 
                 persistence candidate gene 1 
               
               
                 THRB 
                 NM_000461.4 
                 
                   Homo 
                 
                 thyroid hormone receptor, beta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 THRB 
                 NM_001128176.2 
                 
                   Homo 
                 
                 thyroid hormone receptor, beta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 THRB 
                 NM_001128177.1 
                 
                   Homo 
                 
                 thyroid hormone receptor, beta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 THRB 
                 NM_001252634.1 
                 
                   Homo 
                 
                 thyroid hormone receptor, beta 
               
               
                   
                   
                 
                   sapiens 
                 
                   
               
               
                 THRB 
                 NM_00H13417.1 
                 
                   Mus  
                 
                 thyroid hormone receptor, beta 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 THRB 
                 NM_009380.3 
                 
                   Mus  
                 
                 thyroid hormone receptor, beta 
               
               
                   
                   
                 
                   musculus 
                 
                   
               
               
                 NR1H4 
                 NM_001206977.1 
                 
                   Homo 
                 
                 nuclear receptor subfamily 1, group H, 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_001206978.1 
                 
                   Homo 
                 
                 nuclear receptor subfamily 1, group H, 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_001206979.1 
                 
                   Homo 
                 
                 nuclear receptor subfamily 1, group H,  
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_001206992.1 
                 
                   Homo 
                 
                 nuclear receptor subfamily 1, group H,  
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_001206993.1 
                 
                   Homo 
                 
                 nuclear receptor subfamily 1, group H, 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_005123.3 
                 
                   Homo 
                 
                 nuclear receptor subfamily 1, group H, 
               
               
                   
                   
                 
                   sapiens 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_001163504.1 
                 
                   Mus  
                 
                 nuclear receptor subfamily 1, group H,  
               
               
                   
                   
                 
                   musculus 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_001163700.1 
                 
                   Mus  
                 
                 nuclear receptor subfamily 1, group H,  
               
               
                   
                   
                 
                   musculus 
                 
                 member 4 
               
               
                 NR1H4 
                 NM_009108.2 
                 
                   Mus  
                 
                 nuclear receptor subfamily 1, group H,  
               
               
                   
                   
                 
                   musculus 
                 
                 member 4 
               
               
                 PRKAA1 
                 NM_006251.5 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, alpha 1  
               
               
                   
                   
                 
                   sapiens 
                 
                 catalytic subunit 
               
               
                 PRKAA1 
                 NM_206907.3 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, alpha 1 
               
               
                   
                   
                 
                   sapiens 
                 
                 catalytic subunit 
               
               
                 PRKAA1 
                 NM_001013367.3 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, alpha 1  
               
               
                   
                   
                 
                   musculus 
                 
                 catalytic subunit 
               
               
                 PRKAA2 
                 NM_006252.3 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, alpha 2  
               
               
                   
                   
                 
                   sapiens 
                 
                 catalytic subunit 
               
               
                 PRKAA2 
                 NM_178143.2 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, alpha 2 
               
               
                   
                   
                 
                   musculus 
                 
                 catalytic subunit 
               
               
                 PRKAB1 
                 NM_006253.4 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, beta 1  
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAB1 
                 NM_031869.2 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, beta 1 
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                 PRKAB2 
                 NM_005399.4 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, beta 2  
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAB2 
                 NM_182997.2 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, beta 2 
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                 PRKAG1 
                 NM_001206709.1 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 1 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG1 
                 NM_001206710.1 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 1 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG1 
                 NM_002733.4 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 1  
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG1 
                 NM_016781.2 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, gamma 1 
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_001040633.1 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 2 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_001304527.1 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 2  
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_001304531.1 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 2 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_016203.3 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 2 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_024429.1 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 2 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_001170555.1 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, gamma 2 
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_001170556.1 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, gamma 2  
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                 PRKAG2 
                 NM_145401.2 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, gamma 2  
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                 PRKAG3 
                 NM_017431.2 
                 
                   Homo 
                 
                 protein kinase, AMP-activated, gamma 3 
               
               
                   
                   
                 
                   sapiens 
                 
                 non-catalytic subunit 
               
               
                 PRKAG3 
                 NM_153744.3 
                 
                   Mus  
                 
                 protein kinase, AMP-activated, gamma 3 
               
               
                   
                   
                 
                   musculus 
                 
                 non-catalytic subunit 
               
               
                   
               
            
           
         
       
     
     Methods of modulating (e.g., upregulating or downregulating) gene expression are provided, in some embodiments, that may be carried out in vitro, ex vivo, or in vivo. It is understood that any reference to uses of compounds throughout the description contemplates use of the compound in preparation of a pharmaceutical composition or medicament for use in the treatment of a condition associated with increased or decreased levels or activity of a target gene. Thus, as one nonlimiting example, this aspect of the invention includes use of such single stranded oligonucleotides in the preparation of a medicament for use in the treatment of disease, wherein the treatment involves upregulating or downregulating expression of a target gene. 
     In further aspects of the invention, methods are provided for selecting a candidate oligonucleotide for modulating (e.g., upregulating or downregulating) expression of a target gene. The methods generally involve selecting as a candidate oligonucleotide, a single stranded oligonucleotide comprising a nucleotide sequence that is complementary to a lancRNA or to a chromosomal region that encodes a lancRNA, e.g., a region within 5 kb of a transcriptional boundary of a target gene. In some embodiments, sets of oligonucleotides may be selected that are enriched (e.g., compared with a random selection of oligonucleotides) in oligonucleotides that modulate (e.g., upregulate or downregulate) expression of a target gene. 
     Single Stranded Oligonucleotides for Modulating Expression of a Target Gene 
     In one aspect of the invention, single stranded oligonucleotides complementary to a lancRNA or to a chromosomal region that encodes a lancRNA, e.g., a region within 5 kb of a transcriptional boundary of a target gene, are provided for modulating expression of the target gene in a cell. In some embodiments, expression of the target gene is upregulated or increased. The oligonucleotide may be selected using any of the methods disclosed herein for selecting a candidate oligonucleotide for modulating expression of a target gene. 
     The single stranded oligonucleotide may comprise a region of complementarity that is complementary with a lancRNA or with a chromosomal region that encodes a lancRNA, e.g., a region within 5 kb of a transcriptional boundary of a target gene. The region of complementarity of the single stranded oligonucleotide may be complementary with at least 5, e.g., at least 6, at least 7, at least 8, at least 9, at least 10, at least 15 or more consecutive nucleotides of the lancRNA or chromosomal region that encodes the lancRNA, e.g., a region within 5 kb of a transcriptional boundary of a target gene. 
     The chromosomal region encoding the lancRNA may map to a position in a chromosome between 10 kilobases (e.g., 5 kb, 4, kb, 2 kb, 1 kb, 500 bp, 400 bp, 300 bp, 200 bp, 100 bp) upstream and 10 kilobases (e.g., 5 kb, 4, kb, 2 kb, 1 kb, 500 bp, 400 bp, 300 bp, 200 bp, 100 bp) downstream of a transcriptional start site of the target gene or 10 kilobases (e.g., 5 kb, 4, kb, 2 kb, 1 kb, 500 bp, 400 bp, 300 bp, 200 bp, 100 bp) upstream and 10 kilobases (e.g., 5 kb, 4, kb, 2 kb, 1 kb, 500 bp, 400 bp, 300 bp, 200 bp, 100 bp) downstream of a transcriptional end site of the target gene. 
     The single stranded oligonucleotide may have a sequence that does not contain guanosine nucleotide stretches (e.g., 3 or more, 4 or more, 5 or more, 6 or more consecutive guanosine nucleotides). In some embodiments, oligonucleotides having guanosine nucleotide stretches have increased non-specific binding and/or off-target effects, compared with oligonucleotides that do not have guanosine nucleotide stretches. 
     The single stranded oligonucleotide may have a sequence that has less than a threshold level of sequence identity with every sequence of nucleotides, of equivalent length, that map to a genomic position encompassing or in proximity to an off-target gene. For example, an oligonucleotide may be designed to ensure that it does not have a sequence that maps to genomic positions encompassing or in proximity with all known genes (e.g., all known protein coding genes) other than the target gene. In a similar embodiment, an oligonucleotide may be designed to ensure that it does not have a sequence that maps to any other known lancRNAs. In either case, the oligonucleotide is expected to have a reduced likelihood of having off-target effects. The threshold level of sequence identity may be 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99% or 100% sequence identity. 
     The single stranded oligonucleotide may have a sequence that is has greater than 30% G-C content, greater than 40% G-C content, greater than 50% G-C content, greater than 60% G-C content, greater than 70% G-C content, or greater than 80% G-C content. The single stranded oligonucleotide may have a sequence that has up to 100% G-C content, up to 95% G-C content, up to 90% G-C content, or up to 80% G-C content. In some embodiments in which the oligonucleotide is 8 to 10 nucleotides in length, all but 1, 2, 3, 4, or 5 of the nucleotides of the complementary sequence of the lancRNA are cytosine or guanosine nucleotides. In some embodiments, the sequence of the lancRNA to which the single stranded oligonucleotide is complementary comprises no more than 3 nucleotides selected from adenine and uracil. 
     The single stranded oligonucleotide may be complementary to a chromosome of a different species (e.g., a mouse, rat, rabbit, goat, monkey, etc.) at a position that encompasses or that is in proximity to that species&#39; homolog of a target gene. The single stranded oligonucleotide may be complementary to a human genomic region encompassing or in proximity to the target gene and also be complementary to a mouse genomic region encompassing or in proximity to the mouse homolog of the target gene. Oligonucleotides having these characteristics may be tested in vivo or in vitro for efficacy in multiple species (e.g., human and mouse). This approach also facilitates development of clinical candidates for treating human disease by selecting a species in which an appropriate animal exists for the disease. 
     According to some aspects, single stranded oligonucleotides are provided that have a region of complementarity that is complementarty with (e.g., at least 5 consecutive nucleotides of) a lancRNA of a target gene. In some embodiments, the oligonucleotide has at least one of the following features: a) a sequence that is 5′X-Y-Z, in which X is any nucleotide and in which X is at the 5′ end of the oligonucleotide, Y is a nucleotide sequence of 6 nucleotides in length that is not a human seed sequence of a microRNA, and Z is a nucleotide sequence of 1 to 23 nucleotides in length; b) a sequence that does not comprise three or more consecutive guanosine nucleotides; c) a sequence that has less than a threshold level of sequence identity with every sequence of nucleotides, of equivalent length to the second nucleotide sequence, that are between 50 kilobases upstream of a 5′-end of an off-target gene and 50 kilobases downstream of a 3′-end of the off-target gene; and d) a sequence that has greater than 60% G-C content. In some embodiments, the single stranded oligonucleotide has at least two of features a), b), c), and d), each independently selected. In some embodiments, the single stranded oligonucleotide has at least three of features a), b), c), and d), each independently selected. In some embodiments, the single stranded oligonucleotide has at least four of features a), b), c), and d), each independently selected. In some embodiments, the single stranded oligonucleotide has each of features a), b), c), and d). In certain embodiments, the oligonucleotide has the sequence 5′X-Y-Z, in which the oligonucleotide is 8-50 nucleotides in length. 
     In some embodiments, the region of complementarity of the single stranded oligonucleotide is complementary with 5 to 15, 6 to 15, 7 to 15, 8 to 15, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 8 to 40, or 10 to 50, or 5 to 50, or 5 to 40 bases, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 consecutive nucleotides of a lancRNA. In some embodiments, the region of complementarity is complementary with at least 8 consecutive nucleotides of a lancRNA. 
     Complementary, as the term is used in the art, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of lancRNA, then the single stranded nucleotide and lancRNA are considered to be complementary to each other at that position. The single stranded nucleotide and lancRNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides that can hydrogen bond with each other through their bases. Thus, “complementary” is a term which is used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the single stranded nucleotide and lancRNA. For example, if a base at one position of a single stranded nucleotide is capable of hydrogen bonding with a base at the corresponding position of a lancRNA, then the bases are considered to be complementary to each other at that position. 100% complementarity is not required. 
     The single stranded oligonucleotide may be at least 80% complementary to (optionally one of at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% complementary to) the consecutive nucleotides of a lancRNA. In some embodiments the single stranded oligonucleotide may contain 1, 2 or 3 base mismatches compared to the portion of the consecutive nucleotides of a lancRNA. In some embodiments the single stranded oligonucleotide may have up to 3 mismatches over 15 bases, or up to 2 mismatches over 10 bases. 
     It is understood in the art that a complementary nucleotide sequence need not be 100% complementary to that of its target to be specifically hybridizable. In some embodiments, a complementary nucleic acid sequence for purposes of the present disclosure is specifically hybridizable when binding of the sequence to the target molecule (e.g., lancRNA) interferes with the normal function of the target (e.g., lancRNA) to cause a loss of activity and there is a sufficient degree of complementarity to avoid non-specific binding of the sequence to non-target sequences under conditions in which avoidance of non-specific binding is desired, e.g., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed under suitable conditions of stringency. 
     In some embodiments, the single stranded oligonucleotide is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50 or more nucleotides in length. In some embodiments, the oligonucleotide is 8 to 30 nucleotides in length. 
     In some embodiments, the chromosomal region encoding the lancRNA occurs on the same DNA strand as a gene sequence (sense). In some embodiments, the chromosomal region encoding the lancRNA occurs on the opposite DNA strand as a gene sequence (anti-sense). Oligonucleotides complementary to a lancRNA or the chromosomal region encoding the lancRNA can bind either sense or anti-sense sequences. Base pairings may include both canonical Watson-Crick base pairing and non-Watson-Crick base pairing (e.g., Wobble base pairing and Hoogsteen base pairing). It is understood that for complementary base pairings, adenosine-type bases (A) are complementary to thymidine-type bases (T) or uracil-type bases (U), that cytosine-type bases (C) are complementary to guanosine-type bases (G), and that universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any A, C, U, or T. Inosine (I) has also been considered in the art to be a universal base and is considered complementary to any A, C, U or T. 
     In some embodiments, any one or more thymidine (T) nucleotides (or modified nucleotide thereof) or uridine (U) nucleotides (or a modified nucleotide thereof) in a sequence provided herein, including a sequence provided in the sequence listing, may be replaced with any other nucleotide suitable for base pairing (e.g., via a Watson-Crick base pair) with an adenosine nucleotide. In some embodiments, any one or more thymidine (T) nucleotides (or modified nucleotide thereof) or uridine (U) nucleotides (or a modified nucleotide thereof) in a sequence provided herein, including a sequence provided in the sequence listing, may be suitably replaced with a different pyrimidine nucleotide or vice versa. In some embodiments, any one or more thymidine (T) nucleotides (or modified nucleotide thereof) in a sequence provided herein, including a sequence provided in the sequence listing, may be suitably replaced with a uridine (U) nucleotide (or a modified nucleotide thereof) or vice versa. 
     In some embodiments, GC content of the single stranded oligonucleotide is preferably between about 30-60%. Contiguous runs of three or more Gs or Cs may not be preferable in some embodiments. Accordingly, in some embodiments, the oligonucleotide does not comprise a stretch of three or more guanosine nucleotides. 
     In some embodiments, it has been found that single stranded oligonucleotides disclosed herein may increase expression of mRNA corresponding to the gene by at least about 50% (i.e. 150% of normal or 1.5 fold), or by about 2 fold to about 5 fold. In some embodiments, expression may be increased by at least about 15 fold, 20 fold, 30 fold, 40 fold, 50 fold or 100 fold, or any range between any of the foregoing numbers. It has also been found that increased mRNA expression has been shown to correlate to increased protein expression. 
     In some or any of the embodiments of oligonucleotides described herein, or processes for designing or synthesizing them, the oligonucleotides will upregulate gene expression and may specifically bind or specifically hybridize or be complementary to a lancRNA that is transcribed from the same strand (the sense strand) of a protein coding reference gene. In some or any of the embodiments of oligonucleotides described herein, or processes for designing or synthesizing them, the oligonucleotides will upregulate gene expression and may specifically bind or specifically hybridize or be complementary to a lancRNA that is transcribed from the opposite strand (the antisense strand) of a protein coding reference gene. The oligonucleotide may bind to a region of the lancRNA that is transcribed from a region within or overlaps with an 5′ UTR, 3′ UTR, a translation initiation region, or a translation termination region of a target gene. The oligonucleotide may bind to a region of the lancRNA that is transcribed from a region upstream of an 5′ UTR or a translation initiation region or from a region downstream of a 3′ UTR or a translation termination region of a target gene. 
     The oligonucleotides described herein may be modified, e.g., comprise a modified sugar moiety, a modified internucleoside linkage, a modified nucleotide and/or combinations thereof. 
     Any of the oligonucleotides disclosed herein may be linked to one or more other oligonucleotides disclosed herein by a linker, e.g., a cleavable linker. 
     Method for Selecting Candidate Oligonucleotides for Modulating Expression of a Target Gene 
     Methods are provided herein for selecting a candidate oligonucleotide for modulating (e.g., activating or enhancing) expression of a target gene. The target selection methods may generally involve steps for selecting single stranded oligonucleotides having any of the structural and functional characteristics disclosed herein. Typically, the methods involve one or more steps aimed at identifying oligonucleotides that target a lancRNA that is functionally related to a target gene, for example a lancRNA that regulates expression of a target gene (e.g., in a cis-regulatory manner). In some embodiments, “cis-regulatory manner” means that the lancRNA regulates expression of genes in the locus from which the lancRNA is expressed. 
     Methods of selecting a candidate oligonucleotide may involve selecting a region that encodes a lancRNA that maps to a chromosomal position encompassing or in proximity to a transcriptional boundary of the target gene. The region encoding the lancRNA may map to the strand of the chromosome comprising the sense strand of the target gene, in which case the candidate oligonucleotide is complementary to the sense strand of the target gene (i.e., the oligonucleotide is antisense to the target gene). Alternatively, the region encoding the lancRNA may map to the strand of the chromosome comprising the antisense strand of the target gene, in which case the oligonucleotide is complementary to the antisense strand (the template strand) of the target gene (i.e., the oligonucleotide is sense to the target gene). 
     Methods for selecting a set of candidate oligonucleotides that is enriched in oligonucleotides that modulate (e.g., activate) expression of a target gene may involve selecting one or more regions that encode lancRNAs that map to a chromosomal position that encompasses or that is in proximity to a transcriptional boundary of the target gene and selecting a set of oligonucleotides, in which each oligonucleotide in the set comprises a nucleotide sequence that is complementary with the one or more regions. As used herein, the phrase, “a set of oligonucleotides that is enriched in oligonucleotides that modulate (e.g., activate) expression of” refers to a set of oligonucleotides that has a greater number of oligonucleotides that modulate (e.g., activate) expression of a target gene compared with a random selection of oligonucleotides of the same physicochemical properties (e.g., the same GC content, T m , length etc.) as the enriched set. 
     Where the design and/or synthesis of a single stranded oligonucleotide involves design and/or synthesis of a sequence that is complementary to a nucleic acid or lancRNA described by such sequence information, the skilled person is readily able to determine the complementary sequence, e.g., through understanding of Watson Crick base pairing rules which form part of the common general knowledge in the field. 
     In some embodiments design and/or synthesis of a single stranded oligonucleotide involves manufacture of an oligonucleotide from starting materials by techniques known to those of skill in the art, where the synthesis may be based on a sequence of a lancRNA, a region encoding a lancRNA, or portion thereof. 
     Methods of design and/or synthesis of a single stranded oligonucleotide may involve one or more of the steps of: 
     Identifying and/or selecting a chromosomal region within 5 kb of a transcriptional boundary; 
     Designing a nucleic acid sequence having a desired degree of sequence identity or complementarity to the region or a portion thereof; 
     Synthesizing a single stranded oligonucleotide to the designed sequence; 
     Purifying the synthesized single stranded oligonucleotide; and 
     Optionally mixing the synthesized single stranded oligonucleotide with at least one pharmaceutically acceptable diluent, carrier or excipient to form a pharmaceutical composition or medicament. 
     Single stranded oligonucleotides so designed and/or synthesized may be useful in method of modulating gene expression as described herein. 
     Preferably, single stranded oligonucleotides of the invention are synthesized chemically. Oligonucleotides used to practice this invention can be synthesized in vitro by well-known chemical synthesis techniques. 
     Oligonucleotides of the invention can be stabilized against nucleolytic degradation such as by the incorporation of a modification, e.g., a nucleotide modification. For example, nucleic acid sequences of the invention include a phosphorothioate at least the first, second, or third internucleotide linkage at the 5′ or 3′ end of the nucleotide sequence. As another example, the nucleic acid sequence can include a 2′-modified nucleotide, e.g., a 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O—N-methylacetamido (2′-O-NMA). As another example, the nucleic acid sequence can include at least one 2′-O-methyl-modified nucleotide, and in some embodiments, all of the nucleotides include a 2′-O-methyl modification. In some embodiments, the nucleic acids are “locked,” i.e., comprise nucleic acid analogues in which the ribose ring is “locked” by a methylene bridge connecting the 2′-O atom and the 4′-C atom. 
     It is understood that any of the modified chemistries or formats of single stranded oligonucleotides described herein can be combined with each other, and that one, two, three, four, five, or more different types of modifications can be included within the same molecule. 
     In some embodiments, the method may further comprise the steps of amplifying the synthesized single stranded oligonucleotide, and/or purifying the single stranded oligonucleotide (or amplified single stranded oligonucleotide), and/or sequencing the single stranded oligonucleotide so obtained. 
     As such, the process of preparing a single stranded oligonucleotide may be a process that is for use in the manufacture of a pharmaceutical composition or medicament for use in the treatment of disease, optionally wherein the treatment involves modulating expression of a target gene. 
     In the methods described above a lancRNA may be, or have been, identified, or obtained, by a method that involves a detection of the lancRNA. Exemplary methods include RNase protection assays, FISH (fluorescence in situ hybridization), single molecule imaging, deep and/or targeted next generation sequencing. and Northern blots, which are known in the art. 
     Where the single stranded oligonucleotide is based on a lancRNA sequence, or a portion of such a sequence, it may be based on information about that sequence, e.g., sequence information available in written or electronic form, which may include sequence information contained in publicly available scientific publications or sequence databases. 
     Nucleotide Analogues 
     In some embodiments, the oligonucleotide may comprise at least one ribonucleotide, at least one deoxyribonucleotide, and/or at least one bridged nucleotide. In some embodiments, the oligonucleotide may comprise a bridged nucleotide, such as a locked nucleic acid (LNA) nucleotide, a constrained ethyl (cEt) nucleotide, or an ethylene bridged nucleic acid (ENA) nucleotide. Examples of such nucleotides are disclosed herein and known in the art. In some embodiments, the oligonucleotide comprises a nucleotide analog disclosed in one of the following United States patent or patent application Publications: U.S. Pat. No. 7,399,845, U.S. Pat. No. 7,741,457, U.S. Pat. No. 8,022,193, U.S. Pat. No. 7,569,686, U.S. Pat. No. 7,335,765, U.S. Pat. No. 7,314,923, U.S. Pat. No. 7,335,765, and U.S. Pat. No. 7,816,333, US 20110009471, the entire contents of each of which are incorporated herein by reference for all purposes. The oligonucleotide may have one or more 2′ O-methyl nucleotides. The oligonucleotide may consist entirely of 2′ O-methyl nucleotides. 
     Often the single stranded oligonucleotide has one or more nucleotide analogues. For example, the single stranded oligonucleotide may have at least one nucleotide analogue that results in an increase in T m  of the oligonucleotide in a range of 1° C., 2° C., 3° C., 4° C., or 5° C. compared with an oligonucleotide that does not have the at least one nucleotide analogue. The single stranded oligonucleotide may have a plurality of nucleotide analogues that results in a total increase in T m  of the oligonucleotide in a range of 2° C., 3° C., 4° C., 5° C., 6° C., 7° C., 8° C., 9° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C. or more compared with an oligonucleotide that does not have the nucleotide analogue. 
     The oligonucleotide may be of up to 50 nucleotides in length in which 2 to 10, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 40, 2 to 45, or more nucleotides of the oligonucleotide are nucleotide analogues. The oligonucleotide may be of 8 to 30 nucleotides in length in which 2 to 10, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30 nucleotides of the oligonucleotide are nucleotide analogues. 
     The oligonucleotide may be of 8 to 15 nucleotides in length in which 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14 nucleotides of the oligonucleotide are nucleotide analogues. Optionally, the oligonucleotides may have every nucleotide except 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides modified. 
     The oligonucleotide may consist entirely of bridged nucleotides (e.g., LNA nucleotides, cEt nucleotides, ENA nucleotides). The oligonucleotide may comprise alternating deoxyribonucleotides and 2′-fluoro-deoxyribonucleotides. The oligonucleotide may comprise alternating deoxyribonucleotides and 2′-O-methyl nucleotides. The oligonucleotide may comprise alternating deoxyribonucleotides and ENA nucleotide analogues. The oligonucleotide may comprise alternating deoxyribonucleotides and LNA nucleotides. The oligonucleotide may comprise alternating LNA nucleotides and 2′-O-methyl nucleotides. The oligonucleotide may have a 5′ nucleotide that is a bridged nucleotide (e.g., a LNA nucleotide, cEt nucleotide, ENA nucleotide). The oligonucleotide may have a 5′ nucleotide that is a deoxyribonucleotide. 
     The oligonucleotide may comprise deoxyribonucleotides flanked by at least one bridged nucleotide (e.g., a LNA nucleotide, cEt nucleotide, ENA nucleotide) on each of the 5′ and 3′ ends of the deoxyribonucleotides. The oligonucleotide may comprise deoxyribonucleotides flanked by 1, 2, 3, 4, 5, 6, 7, 8 or more bridged nucleotides (e.g., LNA nucleotides, cEt nucleotides, ENA nucleotides) on each of the 5′ and 3′ ends of the deoxyribonucleotides. The 3′ position of the oligonucleotide may have a 3′ hydroxyl group. The 3′ position of the oligonucleotide may have a 3′ thiophosphate. 
     The oligonucleotide may be conjugated with a label. For example, the oligonucleotide may be conjugated with a biotin moiety, cholesterol, Vitamin A, folate, sigma receptor ligands, aptamers, peptides, such as CPP, hydrophobic molecules, such as lipids, ASGPR or dynamic polyconjugates and variants thereof at its 5′ or 3′ end. 
     Preferably the single stranded oligonucleotide comprises one or more modifications comprising: a modified sugar moiety, and/or a modified internucleoside linkage, and/or a modified nucleotide and/or combinations thereof. It is not necessary for all positions in a given oligonucleotide to be uniformly modified, and in fact more than one of the modifications described herein may be incorporated in a single oligonucleotide or even at within a single nucleoside within an oligonucleotide. 
     In some embodiments, the single stranded oligonucleotides are chimeric oligonucleotides that contain two or more chemically distinct regions, each made up of at least one nucleotide. These oligonucleotides typically contain at least one region of modified nucleotides that confers one or more beneficial properties (such as, for example, increased nuclease resistance, increased uptake into cells, increased binding affinity for the target) and a region that is a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. Chimeric single stranded oligonucleotides of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures comprise, but are not limited to, U.S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, each of which is herein incorporated by reference. 
     In some embodiments, the single stranded oligonucleotide comprises at least one nucleotide modified at the 2′ position of the sugar, most preferably a 2′-O-alkyl, 2′-O-alkyl-O-alkyl or 2′-fluoro-modified nucleotide. In other preferred embodiments, RNA modifications include 2′-fluoro, 2′-amino and 2′ O-methyl modifications on the ribose of pyrimidines, abasic residues or an inverted base at the 3′ end of the RNA. Such modifications are routinely incorporated into oligonucleotides and these oligonucleotides have been shown to have a higher Tm (i.e., higher target binding affinity) than 2′-deoxyoligonucleotides against a given target. 
     A number of nucleotide and nucleoside modifications have been shown to make the oligonucleotide into which they are incorporated more resistant to nuclease digestion than the native oligodeoxynucleotide; these modified oligos survive intact for a longer time than unmodified oligonucleotides. Specific examples of modified oligonucleotides include those comprising modified backbones, for example, phosphorothioates, phosphotriesters, methyl phosphonates, short chain alkyl or cycloalkyl intersugar linkages or short chain heteroatomic or heterocyclic intersugar linkages. Most preferred are oligonucleotides with phosphorothioate backbones and those with heteroatom backbones, particularly CH 2 —NH—O—CH 2 , CH, ˜N(CH 3 )˜O˜CH 2  (known as a methylene(methylimino) or MMI backbone, CH 2 —O—N(CH 3 )—CH 2 , CH 2 —N(CH 3 )—N(CH 3 )—CH 2  and O—N(CH 3 )—CH 2 —CH 2  backbones, wherein the native phosphodiester backbone is represented as O—P—O—CH); amide backbones (see De Mesmaeker et al. Ace. Chem. Res. 1995, 28:366-374); morpholino backbone structures (see Summerton and Weller, U.S. Pat. No. 5,034,506); peptide nucleic acid (PNA) backbone (wherein the phosphodiester backbone of the oligonucleotide is replaced with a polyamide backbone, the nucleotides being bound directly or indirectly to the aza nitrogen atoms of the polyamide backbone, see Nielsen et al., Science 1991, 254, 1497). Phosphorus-containing linkages include, but are not limited to, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates comprising 3′alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates comprising 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′; see U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455, 233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563, 253; 5,571,799; 5,587,361; and 5,625,050. 
     Morpholino-based oligomeric compounds are described in Dwaine A. Braasch and David R. Corey, Biochemistry, 2002, 41(14), 4503-4510); Genesis, volume 30, issue 3, 2001; Heasman, J., Dev. Biol., 2002, 243, 209-214; Nasevicius et al., Nat. Genet., 2000, 26, 216-220; Lacerra et al., Proc. Natl. Acad. Sci., 2000, 97, 9591-9596; and U.S. Pat. No. 5,034,506, issued Jul. 23, 1991. In some embodiments, the morpholino-based oligomeric compound is a phosphorodiamidate morpholino oligomer (PMO) (e.g., as described in Iverson, Curr. Opin. Mol. Ther., 3:235-238, 2001; and Wang et al., J. Gene Med., 12:354-364, 2010; the disclosures of which are incorporated herein by reference in their entireties). 
     Cyclohexenyl nucleic acid oligonucleotide mimetics are described in Wang et al., J. Am. Chem. Soc., 2000, 122, 8595-8602. 
     Modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These comprise those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts; see U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264, 562; 5, 264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439, each of which is herein incorporated by reference. 
     Modified oligonucleotides are also known that include oligonucleotides that are based on or constructed from arabinonucleotide or modified arabinonucleotide residues. Arabinonucleosides are stereoisomers of ribonucleosides, differing only in the configuration at the 2′-position of the sugar ring. In some embodiments, a 2′-arabino modification is 2′-F arabino. In some embodiments, the modified oligonucleotide is 2′-fluoro-D-arabinonucleic acid (FANA) (as described in, for example, Lon et al., Biochem., 41:3457-3467, 2002 and Min et al., Bioorg. Med. Chem. Lett., 12:2651-2654, 2002; the disclosures of which are incorporated herein by reference in their entireties). Similar modifications can also be made at other positions on the sugar, particularly the 3′ position of the sugar on a 3′ terminal nucleoside or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. 
     PCT Publication No. WO 99/67378 discloses arabinonucleic acids (ANA) oligomers and their analogues for improved sequence specific inhibition of gene expression via association to complementary messenger RNA. 
     Other preferred modifications include ethylene-bridged nucleic acids (ENAs) (e.g., International Patent Publication No. WO 2005/042777, Morita et al., Nucleic Acid Res., Suppl 1:241-242, 2001; Surono et al., Hum. Gene Ther., 15:749-757, 2004; Koizumi, Curr. Opin. Mol. Ther., 8:144-149, 2006 and Horie et al., Nucleic Acids Symp. Ser (Oxf), 49:171-172, 2005; the disclosures of which are incorporated herein by reference in their entireties). Preferred ENAs include, but are not limited to, 2′-0,4′-C-ethylene-bridged nucleic acids. 
     Examples of LNAs are described in WO/2008/043753 and include compounds of the following general formula. 
     
       
         
         
             
             
         
       
     
     where X and Y are independently selected among the groups —O—, 
     —S—, —N(H)—, N(R)—, —CH 2 — or —CH— (if part of a double bond), 
     —CH 2 —O—, —CH 2 —S—, —CH 2 —N(H)—, —CH 2 —N(R)—, —CH 2 —CH 2 — or —CH 2 —CH— (if part of a double bond), 
     —CH═CH—, where R is selected from hydrogen and C 1-4 -alkyl; Z and Z* are independently selected among an internucleoside linkage, a terminal group or a protecting group; B constitutes a natural or non-natural nucleotide base moiety; and the asymmetric groups may be found in either orientation. 
     Preferably, the LNA used in the oligonucleotides described herein comprises at least one LNA unit according any of the formulas 
     
       
         
         
             
             
         
       
     
     wherein Y is —O—, —S—, —NH—, or N(R H ); Z and Z* are independently selected among an internucleoside linkage, a terminal group or a protecting group; B constitutes a natural or non-natural nucleotide base moiety, and RH is selected from hydrogen and C 1-4 -alkyl. 
     In some embodiments, the Locked Nucleic Acid (LNA) used in the oligonucleotides described herein comprises at least one Locked Nucleic Acid (LNA) unit according any of the formulas shown in Scheme 2 of PCT/DK2006/000512. 
     In some embodiments, the LNA used in the oligomer of the invention comprises internucleoside linkages selected from —O—P(O) 2 —O—, —O—P(O,S)—O—, —O—P(S) 2 —O—, —S—P(O) 2 —O—, —S—P(O,S)—O—, —S—P(S) 2 —O—, —O—P(O) 2 —S—, —O—P(O,S)—S—, —S—P(O) 2 —S—, —O—PO(R H )—O—, O—PO(OCH 3 )—O—, —O—PO(NR H )—O—, —O—PO(OCH 2 CH 2 S—R)—O—, —O—PO(BH 3 )—O—, —O—PO(NHR H )—O—, —O—P(O) 2 —NR H —, —NR H —P(O) 2 —O—, —NR H —CO—O—, where R H  is selected from hydrogen and C 1-4 -alkyl. 
     Specifically preferred LNA units are shown in scheme 2: 
     
       
         
         
             
             
         
       
     
     The term “thio-LNA” comprises a locked nucleotide in which at least one of X or Y in the general formula above is selected from S or —CH 2 —S—. Thio-LNA can be in both beta-D and alpha-L-configuration. 
     The term “amino-LNA” comprises a locked nucleotide in which at least one of X or Y in the general formula above is selected from —N(H)—, N(R)—, CH 2 —N(H)—, and —CH 2 —N(R)— where R is selected from hydrogen and C 1-4 -alkyl. Amino-LNA can be in both beta-D and alpha-L-configuration. 
     The term “oxy-LNA” comprises a locked nucleotide in which at least one of X or Y in the general formula above represents —O— or —CH 2 —O—. Oxy-LNA can be in both beta-D and alpha-L-configuration. 
     The term “ena-LNA” comprises a locked nucleotide in which Y in the general formula above is —CH 2 —O— (where the oxygen atom of —CH 2 —O— is attached to the 2′-position relative to the base B). 
     LNAs are described in additional detail herein. 
     One or more substituted sugar moieties can also be included, e.g., one of the following at the 2′ position: OH, SH, SCH 3 , F, OCN, OCH 3 OCH 3 , OCH 3 O(CH 2 )n CH 3 , O(CH 2 )n NH 2  or O(CH 2 )n CH 3  where n is from 1 to about 10; C1 to C10 lower alkyl, alkoxyalkoxy, substituted lower alkyl, alkaryl or aralkyl; Cl; Br; CN; CF 3 ; OCF 3 ; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; SOCH 3 ; SO 2 CH 3 ; ONO 2 ; NO 2 ; N 3 ; NH2; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; an RNA cleaving group; a reporter group; an intercalator; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy [2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl)] (Martin et al, HeIv. Chim. Acta, 1995, 78, 486). Other preferred modifications include 2′-methoxy (2′-O—CH 3 ), 2′-propoxy (2′-OCH 2 CH 2 CH 3 ) and 2′-fluoro (2′-F). Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide and the 5′ position of 5′ terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyls in place of the pentofuranosyl group. 
     Single stranded oligonucleotides can also include, additionally or alternatively, nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include adenine (A), guanine (G), thymine (T), cytosine (C) and uracil (U). Modified nucleobases include nucleobases found only infrequently or transiently in natural nucleic acids, e.g., hypoxanthine, 6-methyladenine, 5-Me pyrimidines, particularly 5-methylcytosine (also referred to as 5-methyl-2′ deoxycytosine and often referred to in the art as 5-Me-C), 5-hydroxymethylcytosine (HMC), glycosyl HMC and gentobiosyl HMC, isocytosine, pseudoisocytosine, as well as synthetic nucleobases, e.g., 2-aminoadenine, 2-(methylamino)adenine, 2-(imidazolylalkyl)adenine, 2-(aminoalklyamino)adenine or other heterosubstituted alkyladenines, 2-thiouracil, 2-thiothymine, 5-bromouracil, 5-hydroxymethyluracil, 5-propynyluracil, 8-azaguanine, 7-deazaguanine, N6 (6-aminohexyl)adenine, 6-aminopurine, 2-aminopurine, 2-chloro-6-aminopurine and 2,6-diaminopurine or other diaminopurines. See, e.g., Kornberg, “DNA Replication,” W. H. Freeman &amp; Co., San Francisco, 1980, pp 75-′7′7; and Gebeyehu, G., et al. Nucl. Acids Res., 15:4513 (1987)). A “universal” base known in the art, e.g., inosine, can also be included. 5-Me-C substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, in Crooke, and Lebleu, eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and may be used as base substitutions. 
     It is not necessary for all positions in a given oligonucleotide to be uniformly modified, and in fact more than one of the modifications described herein may be incorporated in a single oligonucleotide or even at within a single nucleoside within an oligonucleotide. 
     In some embodiments, both a sugar and an internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, for example, an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al, Science, 1991, 254, 1497-1500. 
     Single stranded oligonucleotides can also include one or more nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases comprise the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases comprise other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudo-uracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylquanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. In some embodiments, a cytosine is substituted with a 5-methylcytosine. In some embodiments, an oligonucleotide has 2, 3, 4, 5, 6, 7, or more cytosines substituted with 5-methylcytosines. In some embodiments, an oligonucleotide does not have 2, 3, 4, 5, 6, 7, or more consecutive 5-methylcytosines. In some embodiments, an LNA cytosine nucleotide is replaced with an LNA 5-methylcytosine nucleotide. 
     Further, nucleobases comprise those disclosed in U.S. Pat. No. 3,687,808, those disclosed in “The Concise Encyclopedia of Polymer Science And Engineering”, pages 858-859, Kroschwitz, ed. John Wiley &amp; Sons, 1990; those disclosed by Englisch et al., Angewandle Chemie, International Edition, 1991, 30, page 613, and those disclosed by Sanghvi, Chapter 15, Antisense Research and Applications,” pages 289-302, Crooke, and Lebleu, eds., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, comprising 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2&lt;0&gt;C (Sanghvi, et al., eds, “Antisense Research and Applications,” CRC Press, Boca Raton, 1993, pp. 276-278) and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications. Modified nucleobases are described in U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos. 4,845,205; 5,130,302; 5,134,066; 5,175, 273; 5, 367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,596,091; 5,614,617; 5,750,692, and 5,681,941, each of which is herein incorporated by reference. 
     In some embodiments, the single stranded oligonucleotides are chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution, or cellular uptake of the oligonucleotide. For example, one or more single stranded oligonucleotides, of the same or different types, can be conjugated to each other; or single stranded oligonucleotides can be conjugated to targeting moieties with enhanced specificity for a cell type or tissue type. Such moieties include, but are not limited to, lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al, Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Mancharan et al., Nucleosides &amp; Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-t oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937). See also U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552, 538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486, 603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762, 779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082, 830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5, 245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391, 723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5, 565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599, 928 and 5,688,941, each of which is herein incorporated by reference. 
     These moieties or conjugates can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugate groups include cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve uptake, enhance resistance to degradation, and/or strengthen sequence-specific hybridization with the target nucleic acid. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve uptake, distribution, metabolism or excretion of the compounds of the present invention. Representative conjugate groups are disclosed in International Patent Application No. PCT/US92/09196, filed Oct. 23, 1992, and U.S. Pat. No. 6,287,860, which are incorporated herein by reference. Conjugate moieties include, but are not limited to, lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-5-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxy cholesterol moiety. See, e.g., U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941. 
     In some embodiments, single stranded oligonucleotide modification include modification of the 5′ or 3′ end of the oligonucleotide. In some embodiments, the 3′ end of the oligonucleotide comprises a hydroxyl group or a thiophosphate. It should be appreciated that additional molecules (e.g. a biotin moiety or a fluorophor) can be conjugated to the 5′ or 3′ end of the single stranded oligonucleotide. In some embodiments, the single stranded oligonucleotide comprises a biotin moiety conjugated to the 5′ nucleotide. 
     In some embodiments, the single stranded oligonucleotide comprises locked nucleic acids (LNA), ENA modified nucleotides, 2′-O-methyl nucleotides, or 2′-fluoro-deoxyribonucleotides. In some embodiments, the single stranded oligonucleotide comprises alternating deoxyribonucleotides and 2′-fluoro-deoxyribonucleotides. In some embodiments, the single stranded oligonucleotide comprises alternating deoxyribonucleotides and 2′-O-methyl nucleotides. In some embodiments, the single stranded oligonucleotide comprises alternating deoxyribonucleotides and ENA modified nucleotides. In some embodiments, the single stranded oligonucleotide comprises alternating deoxyribonucleotides and locked nucleic acid nucleotides. In some embodiments, the single stranded oligonucleotide comprises alternating locked nucleic acid nucleotides and 2′-O-methyl nucleotides. 
     In some embodiments, the 5′ nucleotide of the oligonucleotide is a deoxyribonucleotide. In some embodiments, the 5′ nucleotide of the oligonucleotide is a locked nucleic acid nucleotide. In some embodiments, the nucleotides of the oligonucleotide comprise deoxyribonucleotides flanked by at least one locked nucleic acid nucleotide on each of the 5′ and 3′ ends of the deoxyribonucleotides. In some embodiments, the nucleotide at the 3′ position of the oligonucleotide has a 3′ hydroxyl group or a 3′ thiophosphate. 
     In some embodiments, the single stranded oligonucleotide comprises phosphorothioate internucleotide linkages. In some embodiments, the single stranded oligonucleotide comprises phosphorothioate internucleotide linkages between at least two nucleotides. In some embodiments, the single stranded oligonucleotide comprises phosphorothioate internucleotide linkages between all nucleotides. 
     It should be appreciated that the single stranded oligonucleotide can have any combination of modifications as described herein. 
     In some embodiments, an oligonucleotide described herein may be a mixmer or comprise a mixmer sequence pattern. The term ‘mixmer’ refers to oligonucleotides which comprise both naturally and non-naturally occurring nucleotides or comprise two different types of non-naturally occurring nucleotides. Mixmers are generally known in the art to have a higher binding affinity than unmodified oligonucleotides and may be used to specifically bind a target molecule, e.g., to block a binding site on the target molecule. Generally, mixmers do not recruit an RNAse to the target molecule and thus do not promote cleavage of the target molecule. Accordingly, in some embodiments, an oligonucleotide provided herein may be cleavage promoting (e.g., an siRNA or gapmer) or not cleavage promoting (e.g., a mixmer, siRNA, single stranded RNA or double stranded RNA). 
     In some embodiments, the mixmer comprises or consists of a repeating pattern of nucleotide analogues and naturally occurring nucleotides, or one type of nucleotide analogue and a second type of nucleotide analogue. However, it is to be understood that the mixmer need not comprise a repeating pattern and may instead comprise any arrangement of nucleotide analogues and naturally occurring nucleotides or any arrangement of one type of nucleotide analogue and a second type of nucleotide analogue. The repeating pattern, may, for instance be every second or every third nucleotide is a nucleotide analogue, such as LNA, and the remaining nucleotides are naturally occurring nucleotides, such as DNA, or are a 2′ substituted nucleotide analogue such as 2′MOE or 2′ fluoro analogues, or any other nucleotide analogues described herein. It is recognised that the repeating pattern of nucleotide analogues, such as LNA units, may be combined with nucleotide analogues at fixed positions—e.g. at the 5′ or 3′ termini. 
     In some embodiments, the mixmer does not comprise a region of more than 5, more than 4, more than 3, or more than 2 consecutive naturally occurring nucleotides, such as DNA nucleotides. In some embodiments, the mixmer comprises at least a region consisting of at least two consecutive nucleotide analogues, such as at least two consecutive LNAs. In some embodiments, the mixmer comprises at least a region consisting of at least three consecutive nucleotide analogue units, such as at least three consecutive LNAs. 
     In some embodiments, the mixmer does not comprise a region of more than 7, more than 6, more than 5, more than 4, more than 3, or more than 2 consecutive nucleotide analogues, such as LNAs. It is to be understood that the LNA units may be replaced with other nucleotide analogues, such as those referred to herein. 
     In some embodiments, the mixmer comprises at least one nucleotide analogue in one or more of six consecutive nucleotides. The substitution pattern for the nucleotides may be selected from the group consisting of Xxxxxx, xXxxxx, xxXxxx, xxxXxx, xxxxXx and xxxxxX, wherein “X” denotes a nucleotide analogue, such as an LNA, and “x” denotes a naturally occurring nucleotide, such as DNA or RNA. 
     In some embodiments, the mixmer comprises at least two nucleotide analogues in one or more of six consecutive nucleotides. The substitution pattern for the nucleotides may be selected from the group consisting of XXxxxx, XxXxxx, XxxXxx, XxxxXx, XxxxxX, xXXxxx, xXxXxx, xXxxXx, xXxxxX, xxXXxx, xxXxXx, xxXxxX, xxxXXx, xxxXxX and xxxxXX, wherein “X” denotes a nucleotide analogue, such as an LNA, and “x” denotes a naturally occurring nucleotide, such as DNA or RNA. In some embodiments, the substitution pattern for the nucleotides may be selected from the group consisting of XxXxxx, XxxXxx, XxxxXx, XxxxxX, xXxXxx, xXxxXx, xXxxxX, xxXxXx, xxXxxX and xxxXxX. In some embodiments, the substitution pattern is selected from the group consisting of xXxXxx, xXxxXx, xXxxxX, xxXxXx, xxXxxX and xxxXxX. In some embodiments, the substitution pattern is selected from the group consisting of xXxXxx, xXxxXx and xxXxXx. In some embodiments, the substitution pattern for the nucleotides is xXxXxx. 
     In some embodiments, the mixmer comprises at least three nucleotide analogues in one or more of six consecutive nucleotides. The substitution pattern for the nucleotides may be selected from the group consisting of XXXxxx, xXXXxx, xxXXXx, xxxXXX, XXxXxx, XXxxXx, XXxxxX, xXXxXx, xXXxxX, xxXXxX, XxXXxx, XxxXXx, XxxxXX, xXxXXx, xXxxXX, xxXxXX, xXxXxX and XxXxXx, wherein “X” denotes a nucleotide analogue, such as an LNA, and “x” denotes a naturally occuring nucleotide, such as DNA or RNA. In some embodiments, the substitution pattern for the nucleotides is selected from the group consisting of XXxXxx, XXxxXx, XXxxxX, xXXxXx, xXXxxX, xxXXxX, XxXXxx, XxxXXx, XxxxXX, xXxXXx, xXxxXX, xxXxXX, xXxXxX and XxXxXx. In some embodiments, the substitution pattern for the nucleotides is selected from the group consisting of xXXxXx, xXXxxX, xxXXxX, xXxXXx, xXxxXX, xxXxXX and xXxXxX. n some embodiments, the substitution pattern for the nucleotides is xXxXxX or XxXxXx. In some embodiments, the substitution pattern for the nucleotides is xXxXxX. 
     In some embodiments, the mixmer comprises at least four nucleotide analogues in one or more of six consecutive nucleotides. The substitution pattern for the nucleotides may be selected from the group consisting of xXXXX, xXxXXX, xXXxXX, xXXXxX, xXXXXx, XxxXXX, XxXxXX, XxXXxX, XxXXXx, XXxxXX, XXxXxX, XXxXXx, XXXxxX, XXXxXx and XXXXxx, wherein “X” denotes a nucleotide analogue, such as an LNA, and “x” denotes a naturally occurring nucleotide, such as DNA or RNA. 
     In some embodiments, the mixmer comprises at least five nucleotide analogues in one or more of six consecutive nucleotides. The substitution pattern for the nucleotides may be selected from the group consisting of xXXXXX, XxXXXX, XXxXXX, XXXxXX, XXXXxX and XXXXXx, wherein “X” denotes a nucleotide analogue, such as an LNA, and “x” denotes a naturally occurring nucleotide, such as DNA or RNA. 
     The oligonucleotide may comprise a nucleotide sequence having one or more of the following modification patterns. 
     (a) (X)Xxxxxx, (X)xXxxxx, (X)xxXxxx, (X)xxxXxx, (X)xxxxXx and (X)xxxxxX, 
     (b) (X)XXxxxx, (X)XxXxxx, (X)XxxXxx, (X)XxxxXx, (X)XxxxxX, (X)xXXxxx, (X)xXxXxx, (X)xXxxXx, (X)xXxxxX, (X)xxXXxx, (X)xxXxXx, (X)xxXxxX, (X)xxxXXx, (X)xxxXxX and (X)xxxxXX, 
     (c) (X)XXXxxx, (X)xXXXxx, (X)xxXXXx, (X)xxxXXX, (X)XXxXxx, (X)XXxxXx, (X)XXxxxX, (X)xXXxXx, (X)xXXxxX, (X)xxXXxX, (X)XxXXxx, (X)XxxXXx (X)XxxxXX, (X)xXxXXx, (X)xXxxXX, (X)xxXxXX, (X)xXxXxX and (X)XxXxXx, 
     (d) (X)xxXXX, (X)xXxXXX, (X)xXXxXX, (X)xXXXxX, (X)xXXXXx, (X)XxxXXXX, (X)XxXxXX, (X)XxXXxX, (X)XxXXx, (X)XXxxXX, (X)XXxXxX, (X)XXxXXx, (X)XXXxxX, (X)XXXxXx, and (X)XXXXxx, 
     (e) (X)xXXXXX, (X)XxXXXX, (X)XXxXXX, (X)XXXxXX, (X)XXXXxX and (X)XXXXXx, and 
     (f) XXXXXX, XxXXXXX, XXxXXXX, XXXxXXX, XXXXxXX, XXXXXxX and XXXXXXx, in which “X” denotes a nucleotide analogue, (X) denotes an optional nucleotide analogue, and “x” denotes a DNA or RNA nucleotide unit. Each of the above listed patterns may appear one or more times within an oligonucleotide, alone or in combination with any of the other disclosed modification patterns. 
     In some embodiments, the mixmer contains a modified nucleotide, e.g., an LNA, at the 5′ end. In some embodiments, the mixmer contains a modified nucleotide, e.g., an LNA, at the first two positions, counting from the 5′ end. 
     In some embodiments, the mixmer is incapable of recruiting RNAseH. Oligonucleotides that are incapable of recruiting RNAseH are well known in the literature, in example see WO2007/112754, WO2007/112753, or PCT/DK2008/000344. Mixmers may be designed to comprise a mixture of affinity enhancing nucleotide analogues, such as in non-limiting example LNA nucleotides and 2′-O-methyl nucleotides. In some embodiments, the mixmer comprises modified internucleoside linkages (e.g., phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. 
     A mixmer may be produced using any method known in the art or described herein. Representative U.S. patents, U.S. patent publications, and PCT publications that teach the preparation of mixmers include U.S. patent publication Nos. US20060128646, US20090209748, US20090298916, US20110077288, and US20120322851, and U.S. Pat. No. 7,687,617. 
     In some embodiments, the oligonucleotide is a gapmer. A gapmer oligonucleotide generally has the formula 5′-X-Y-Z-3′, with X and Z as flanking regions around a gap region Y. In some embodiments, the Y region is a contiguous stretch of nucleotides, e.g., a region of at least 6 DNA nucleotides, which are capable of recruiting an RNAse, such as RNAseH. Without wishing to be bound by theory, it is thought that the gapmer binds to the target nucleic acid, at which point an RNAse is recruited and can then cleave the target nucleic acid. In some embodiments, the Y region is flanked both 5′ and 3′ by regions X and Z comprising high-affinity modified nucleotides, e.g., 1-6 modified nucleotides. Exemplary modified oligonucleotides include, but are not limited to, 2′ MOE or 2′OMe or Locked Nucleic Acid bases (LNA). The flanks X and Z may be have a of length 1-20 nucleotides, preferably 1-8 nucleotides and even more preferred 1-5 nucleotides. The flanks X and Z may be of similar length or of dissimilar lengths. The gap-segment Y may be a nucleotide sequence of length 5-20 nucleotides, preferably 6-12 nucleotides and even more preferred 6-10 nucleotides. In some aspects, the gap region of the gapmer oligonucleotides of the invention may contain modified nucleotides known to be acceptable for efficient RNase H action in addition to DNA nucleotides, such as C4′-substituted nucleotides, acyclic nucleotides, and arabino-configured nucleotides. In some embodiments, the gap region comprises one or more unmodified internucleosides. In some embodiments, one or both flanking regions each independently comprise one or more phosphorothioate internucleoside linkages (e.g., phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. In some embodiments, the gap region and two flanking regions each independently comprise modified internucleoside linkages (e.g., phosphorothioate internucleoside linkages or other linkages) between at least two, at least three, at least four, at least five or more nucleotides. 
     A gapmer may be produced using any method known in the art or described herein. Representative U.S. patents, U.S. patent publications, and PCT publications that teach the preparation of gapmers include, but are not limited to, U.S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; 5,700,922; 5,898,031; 7,432,250; and 7,683,036; U.S. patent publication Nos. US20090286969, US20100197762, and US20110112170; and PCT publication Nos. WO2008049085 and WO2009090182, each of which is herein incorporated by reference in its entirety. 
     In some embodiments, an oligonucleotide described herein comprises a synthetic cap, e.g., to increase efficiency of translation, RNA half-life and/or function within cells. Synthetic caps are known in the art. Exemplary synthetic caps include, but are not limited to, N7-Methyl-Guanosine-5′-Triphosphate-5′-Guanosine, Guanosine-5′-Triphosphate-5*-Guanosine, N7-Methyl-3′-O-Methyl-Guanosine-5′-Triphosphate-5′-Guanosine (see, e.g., products available from TrilinkBiotech), and N7-benzylated dinucleoside tetraphosphate analogs (see, e.g., Grudzien et al. Novel cap analogs for in vitro synthesis of mRNAs with high translational efficiency. RNA. 2004 September; 10(9): 1479-1487). 
     Methods for Modulating Gene Expression 
     In one aspect, the invention relates to methods for modulating (e.g., upregulating or downregulating) gene expression in a cell (e.g., a cell for which levels of the target gene are reduced or enhanced) for research purposes (e.g., to study the function of the gene in the cell). In another aspect, the invention relates to methods for modulating gene expression in a cell (e.g., a cell for which levels of the target gene are reduced or enhanced) for gene or epigenetic therapy. The cells can be in vitro, ex vivo, or in vivo (e.g., in a subject who has a disease resulting from reduced expression or activity of a target gene. In some embodiments, methods for modulating gene expression in a cell comprise delivering a single stranded oligonucleotide as described herein. In some embodiments, delivery of the single stranded oligonucleotide to the cell results in a level of expression of gene that is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more greater than a level of expression of gene in a control cell to which the single stranded oligonucleotide has not been delivered. In certain embodiments, delivery of the single stranded oligonucleotide to the cell results in a level of expression of gene that is at least 50% greater than a level of expression of gene in a control cell to which the single stranded oligonucleotide has not been delivered. In some embodiments, delivery of the single stranded oligonucleotide to the cell results in a level of expression of gene that is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more less than a level of expression of gene in a control cell to which the single stranded oligonucleotide has not been delivered. 
     In another aspect of the invention, methods comprise administering to a subject (e.g. a human) a composition comprising a single stranded oligonucleotide as described herein to increase protein levels in the subject. In some embodiments, the increase in protein levels is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or more, higher than the amount of a protein in the subject before administering. 
     In another aspect of the invention, methods comprise administering to a subject (e.g. a human) a composition comprising a single stranded oligonucleotide as described herein to decrease protein levels in the subject. In some embodiments, the decrease in protein levels is a decrease of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or more, compared to the amount of a protein in the subject before administering. 
     As another example, to increase or decrease expression of a target gene in a cell, the methods include introducing into the cell a single stranded oligonucleotide that is sufficiently complementary to a lancRNA that maps to a genomic position encompassing or in proximity to a transcriptional boundary of the target gene. 
     In another aspect of the invention provides methods of treating a disease or condition associated with decreased levels of expression of a target gene in a subject, the method comprising administering a single stranded oligonucleotide as described herein. Exemplary diseases and condition associated with certain genes are provided in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Examples of diseases or conditions treatable with oligonucleotides  
               
               
                 targeting lancRNAs associated with genes. 
               
            
           
           
               
               
            
               
                 Gene 
                 Disease of conditions 
               
               
                   
               
               
                 FXN 
                 Friedreich&#39;s Ataxia 
               
               
                 SMN 
                 Spinal muscular atrophy (SMA) types I-IV 
               
               
                 UTRN 
                 Muscular dystrophy (MD) (e.g., Duchenne&#39;s muscular dystrophy, 
               
               
                   
                 Becker&#39;s muscular dystrophy, myotonic dystrophy) 
               
               
                 HEMOGLOBIN 
                 Anemia, microcytic anemia, sickle cell anemia and/or thalassemia (e.g., 
               
               
                   
                 alpha-thalassemia, beta-thalaseemia, delta-thalessemia), beta-thalaseemia 
               
               
                   
                 (e.g., thalassemia minor/intermedia/major) 
               
               
                 ATP2A2 
                 Cardiac conditions (e.g., congenital heart disease, aortic aneurysms, 
               
               
                   
                 aortic dissections, arrhythmia, cardiomyopathy, and congestive heart 
               
               
                   
                 failure), Darier-White disease and Acrokeratosis verruciformi 
               
               
                 APOA1/ 
                 Dyslipidemia (e.g. Hyperlipidemia) and atherosclerosis (e.g. coronary 
               
               
                 ABCA1 
                 artery disease (CAD) and myocardial infarction (MI)) 
               
               
                 PTEN 
                 Cancer, such as, leukemias, lymphomas, myelomas, carcinomas, 
               
               
                   
                 metastatic carcinomas, sarcomas, adenomas, nervous system cancers and 
               
               
                   
                 genito-urinary cancers. In some embodiments, the cancer is adult and 
               
               
                   
                 pediatric acute lymphoblastic leukemia, acute myeloid leukemia, 
               
               
                   
                 adrenocortical carcinoma, AIDS-related cancers, anal cancer, cancer of 
               
               
                   
                 the appendix, astrocytoma, basal cell carcinoma, bile duct cancer, 
               
               
                   
                 bladder cancer, bone cancer, osteosarcoma, fibrous histiocytoma, brain 
               
               
                   
                 cancer, brain stem glioma, cerebellar astrocytoma, malignant glioma, 
               
               
                   
                 ependymoma, medulloblastoma, supratentorial primitive 
               
               
                   
                 neuroectodermal tumors, hypothalamic glioma, breast cancer, male 
               
               
                   
                 breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoid tumor, 
               
               
                   
                 carcinoma of unknown origin, central nervous system lymphoma, 
               
               
                   
                 cerebellar astrocytoma, malignant glioma, cervical cancer, childhood 
               
               
                   
                 cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, 
               
               
                   
                 chronic myeloproliferative disorders, colorectal cancer, cutaneous T-cell 
               
               
                   
                 lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing 
               
               
                   
                 family tumors, extracranial germ cell tumor, extragonadal germ cell 
               
               
                   
                 tumor, extrahepatic bile duct cancer, intraocular melanoma, 
               
               
                   
                 retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal 
               
               
                   
                 stromal tumor, extracranial germ cell tumor, extragonadal germ cell 
               
               
                   
                 tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, 
               
               
                   
                 hairy cell leukemia, head and neck cancer, hepatocellular cancer, 
               
               
                   
                 Hodgkin lymphoma, non-Hodgkin lymphoma, hypopharyngeal cancer, 
               
               
                   
                 hypothalamic and visual pathway glioma, intraocular melanoma, islet 
               
               
                   
                 cell tumors, Kaposi sarcoma, kidney cancer, renal cell cancer, laryngeal 
               
               
                   
                 cancer, lip and oral cavity cancer, small cell lung cancer, non-small cell 
               
               
                   
                 lung cancer, primary central nervous system lymphoma, Waldenstrom 
               
               
                   
                 macroglobulinema, malignant fibrous histiocytoma, medulloblastoma, 
               
               
                   
                 melanoma, Merkel cell carcinoma, malignant mesothelioma, squamous 
               
               
                   
                 neck cancer, multiple endocrine neoplasia syndrome, multiple myeloma, 
               
               
                   
                 mycosis fungoides, myelodysplastic syndromes, myeloproliferative 
               
               
                   
                 disorders, chronic myeloproliferative disorders, nasal cavity and 
               
               
                   
                 paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, 
               
               
                   
                 oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid 
               
               
                   
                 cancer, penile cancer, pharyngeal cancer, pheochromocytoma, 
               
               
                   
                 pineoblastoma and supratentorial primitive neuroectodermal tumors, 
               
               
                   
                 pituitary cancer, plasma cell neoplasms, pleuropulmonary blastoma, 
               
               
                   
                 prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, 
               
               
                   
                 soft tissue sarcoma, uterine sarcoma, Sezary syndrome, non-melanoma 
               
               
                   
                 skin cancer, small intestine cancer, squamous cell carcinoma, squamous 
               
               
                   
                 neck cancer, supratentorial primitive neuroectodermal tumors, testicular 
               
               
                   
                 cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, 
               
               
                   
                 transitional cell cancer, trophoblastic tumors, urethral cancer, uterine 
               
               
                   
                 cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms tumor 
               
               
                 BDNF 
                 Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig&#39;s 
               
               
                   
                 disease), Alzheimer&#39;s Disease (AD), and Parkinson&#39;s Disease (PD), 
               
               
                   
                 Neurodegeneration 
               
               
                 MECP2 
                 Rett Syndrome, MECP2-related severe neonatal encephalopathy, 
               
               
                   
                 Angelman syndrome, or PPM-X syndrome 
               
               
                 FOXP3 
                 Diseases or disorders associated with aberrant immune cell (e.g., T cell) 
               
               
                   
                 activation, e.g., autoimmune or inflammatory diseases or disorders. 
               
               
                   
                 Examples of autoimmune diseases and disorders that may be treated 
               
               
                   
                 according to the methods disclosed herein include, but are not limited to, 
               
               
                   
                 Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing 
               
               
                   
                 hemorrhagic leukoencephalitis, Addison&#39;s disease, 
               
               
                   
                 Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing 
               
               
                   
                 spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome 
               
               
                   
                 (APS), Autoimmune angioedema, Autoimmune aplastic anemia, 
               
               
                   
                 Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune 
               
               
                   
                 hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear 
               
               
                   
                 disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, 
               
               
                   
                 Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune 
               
               
                   
                 thrombocytopenic purpura (ATP), Autoimmune thyroid disease, 
               
               
                   
                 Autoimmune urticaria, Axonal &amp; neuronal neuropathies, Balo disease, 
               
               
                   
                 Behcet&#39;s disease, Bullous pemphigoid, Cardiomyopathy, Castleman 
               
               
                   
                 disease, Celiac disease, Chagas disease, Chronic inflammatory 
               
               
                   
                 demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal 
               
               
                   
                 ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial 
               
               
                   
                 pemphigoid/benign mucosal pemphigoid, inflammatory bowel disease 
               
               
                   
                 (e.g., Crohn&#39;s disease or Ulcerative colitis), Cogans syndrome, Cold 
               
               
                   
                 agglutinin disease, Congenital heart block, Coxsackie myocarditis, 
               
               
                   
                 CREST disease, Essential mixed cryoglobulinemia, Demyelinating 
               
               
                   
                 neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic&#39;s 
               
               
                   
                 disease (neuromyelitis optica), Discoid lupus, Dressler&#39;s syndrome, 
               
               
                   
                 Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema 
               
               
                   
                 nodosum, Experimental allergic encephalomyelitis, Evans syndrome, 
               
               
                   
                 Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell 
               
               
                   
                 myocarditis, Glomerulonephritis, Goodpasture&#39;s syndrome, 
               
               
                   
                 Granulomatosis with Polyangiitis (GPA) (formerly called Wegener&#39;s 
               
               
                   
                 Granulomatosis), Graves&#39; disease, Guillain-Barre syndrome, Hashimoto&#39;s 
               
               
                   
                 encephalitis, Hashimoto&#39;s thyroiditis, Hemolytic anemia, Henoch- 
               
               
                   
                 Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, 
               
               
                   
                 Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4- 
               
               
                   
                 related sclerosing disease, Immunoregulatory lipoproteins, Inclusion 
               
               
                   
                 body myositis, Interstitial cystitis, IPEX (Immunodysregulation, 
               
               
                   
                 Polyendocrinopathy, and Enteropathy, X-linked) syndrome, Juvenile 
               
               
                   
                 arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, 
               
               
                   
                 Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic 
               
               
                   
                 vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, 
               
               
                   
                 Linear IgA disease (LAD), systemic lupus erythematosus (SLE), chronic 
               
               
                   
                 Lyme disease, Meniere&#39;s disease, Microscopic polyangiitis, Mixed 
               
               
                   
                 connective tissue disease (MCTD), Mooren&#39;s ulcer, Mucha-Habermann 
               
               
                   
                 disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, 
               
               
                   
                 Neuromyelitis optica (Devic&#39;s), Neutropenia, Ocular cicatricial 
               
               
                   
                 pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS 
               
               
                   
                 (Pediatric Autoimmune Neuropsychiatric Disorders Associated with 
               
               
                   
                 Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal 
               
               
                   
                 nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, 
               
               
                   
                 Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), 
               
               
                   
                 Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, 
               
               
                   
                 Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, 
               
               
                   
                 &amp; III autoimmune polyglandular syndromes, Polymyalgia rheumatica, 
               
               
                   
                 Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy 
               
               
                   
                 syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary 
               
               
                   
                 sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary 
               
               
                   
                 fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds 
               
               
                   
                 phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter&#39;s 
               
               
                   
                 syndrome, Relapsing polychondritis, Restless legs syndrome, 
               
               
                   
                 Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, 
               
               
                   
                 Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren&#39;s 
               
               
                   
                 syndrome, Sperm &amp; testicular autoimmunity, Stiff person syndrome, 
               
               
                   
                 Subacute bacterial endocarditis (SBE), Susac&#39;s syndrome, Sympathetic 
               
               
                   
                 ophthalmia, Takayasu&#39;s arteritis, Temporal arteritis/Giant cell arteritis, 
               
               
                   
                 Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse 
               
               
                   
                 myelitis, Type 1 diabetes, Undifferentiated connective tissue disease 
               
               
                   
                 (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, and 
               
               
                   
                 Wegener&#39;s granulomatosis (also called Granulomatosis with Polyangiitis 
               
               
                   
                 (GPA)). Further examples of autoimmune disease or disorder include 
               
               
                   
                 inflammatory bowel disease (e.g., Crohn&#39;s disease or Ulcerative colitis), 
               
               
                   
                 IPEX syndrome, Multiple sclerosis, Psoriasis, Rheumatoid arthritis, SLE 
               
               
                   
                 or Type 1 diabetes. Examples of inflammatory diseases or disorders that 
               
               
                   
                 may be treated according to the methods disclosed herein include, but are 
               
               
                   
                 not limited to, Acne Vulgaris, Appendicitis, Arthritis, Asthma, 
               
               
                   
                 Atherosclerosis, Allergies (Type 1 Hypersensitivity), Bursitis, Colitis, 
               
               
                   
                 Chronic Prostatitis, Cystitis, Dermatitis, Glomerulonephritis, 
               
               
                   
                 Inflammatory Bowel Disease, Inflammatory Myopathy (e.g., 
               
               
                   
                 Polymyositis, Dermatomyositis, or Inclusion-body Myositis), 
               
               
                   
                 Inflammatory Lung Disease, Interstitial Cystitis, Meningitis, Pelvic 
               
               
                   
                 Inflammatory Disease, Phlebitis, Psoriasis, Reperfusion Injury, 
               
               
                   
                 Rheumatoid Arthritis, Sarcoidosis, Tendonitis, Tonsilitis, Transplant 
               
               
                   
                 Rejection, and Vasculitis. In some embodiments, the inflammatory 
               
               
                   
                 disease or disorder is asthma. 
               
               
                 THRB 
                 Thyroid hormone resistance, mixed dyslipidemia, dyslipidemia, 
               
               
                   
                 hypercholesterolemia 
               
               
                 NR1H4 
                 Byler disease, cholestasis, cholestasis intrahepatic, dyslipidemia, biliary 
               
               
                   
                 cirrhosis primary, fragile x syndrome, hypercholesterolemia, 
               
               
                   
                 atherosclerosis, biliary atresia 
               
               
                 HAMP 
                 Hemochromatosis (juvenile), hemochromatosis , iron overload, 
               
               
                   
                 hereditary hemochromatosis, anemia, inflammation, thalassemia 
               
               
                   
               
            
           
         
       
     
     A subject can include a non-human mammal, e.g. mouse, rat, guinea pig, rabbit, cat, dog, goat, cow, or horse. In preferred embodiments, a subject is a human. Single stranded oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals, including humans. Single stranded oligonucleotides can be useful therapeutic modalities that can be configured to be useful in treatment regimens for the treatment of cells, tissues and animals, especially humans. 
     For therapeutics, an animal, preferably a human, suspected of having a disease or condition is treated by administering single stranded oligonucleotide in accordance with this invention. For example, in one non-limiting embodiment, the methods comprise the step of administering to the animal in need of treatment, a therapeutically effective amount of a single stranded oligonucleotide as described herein. 
     Formulation, Delivery, and Dosing 
     The oligonucleotides described herein can be formulated for administration to a subject for treating a condition or disease associated with increased or decreased levels of a target gene. It should be understood that the formulations, compositions and methods can be practiced with any of the oligonucleotides disclosed herein. 
     The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient (e.g., an oligonucleotide or compound of the invention) which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration, e.g., intradermal or inhalation. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect, e.g. tumor regression. 
     Pharmaceutical formulations of this invention can be prepared according to any method known to the art for the manufacture of pharmaceuticals. Such formulations can contain sweetening agents, flavoring agents, coloring agents and preserving agents. A formulation can be admixtured with nontoxic pharmaceutically acceptable excipients which are suitable for manufacture. Formulations may comprise one or more diluents, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, lyophilized powders, sprays, creams, lotions, controlled release formulations, tablets, pills, gels, on patches, in implants, etc. 
     A formulated single stranded oligonucleotide composition can assume a variety of states. In some examples, the composition is at least partially crystalline, uniformly crystalline, and/or anhydrous (e.g., less than 80, 50, 30, 20, or 10% water). In another example, the single stranded oligonucleotide is in an aqueous phase, e.g., in a solution that includes water. The aqueous phase or the crystalline compositions can, e.g., be incorporated into a delivery vehicle, e.g., a liposome (particularly for the aqueous phase) or a particle (e.g., a microparticle as can be appropriate for a crystalline composition). Generally, the single stranded oligonucleotide composition is formulated in a manner that is compatible with the intended method of administration. 
     In some embodiments, the composition is prepared by at least one of the following methods: spray drying, lyophilization, vacuum drying, evaporation, fluid bed drying, or a combination of these techniques; or sonication with a lipid, freeze-drying, condensation and other self-assembly. 
     A single stranded oligonucleotide preparation can be formulated or administered (together or separately) in combination with another agent, e.g., another therapeutic agent or an agent that stabilizes a single stranded oligonucleotide, e.g., a protein that complexes with single stranded oligonucleotide. Still other agents include chelators, e.g., EDTA (e.g., to remove divalent cations such as Mg 2+ ), salts, RNAse inhibitors (e.g., a broad specificity RNAse inhibitor such as RNAsin) and so forth. 
     In one embodiment, the single stranded oligonucleotide preparation includes another single stranded oligonucleotide, e.g., a second single stranded oligonucleotide that modulates expression of a second gene or a second single stranded oligonucleotide that modulates expression of the first gene. Still other preparation can include at least 3, 5, ten, twenty, fifty, or a hundred or more different single stranded oligonucleotide species. Such single stranded oligonucleotides can mediated gene expression with respect to a similar number of different genes. In one embodiment, the single stranded oligonucleotide preparation includes at least a second therapeutic agent (e.g., an agent other than an oligonucleotide). 
     Route of Delivery 
     A composition that includes a single stranded oligonucleotide can be delivered to a subject by a variety of routes. Exemplary routes include: intravenous, intradermal, topical, rectal, parenteral, anal, intravaginal, intranasal, pulmonary, ocular, and oral. The term “therapeutically effective amount” is the amount of oligonucleotide present in the composition that is needed to provide the desired level of target gene expression in the subject to be treated to give the anticipated physiological response. The term “physiologically effective amount” is that amount delivered to a subject to give the desired palliative or curative effect. The term “pharmaceutically acceptable carrier” means that the carrier can be administered to a subject with no significant adverse toxicological effects to the subject. 
     The single stranded oligonucleotide molecules of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically include one or more species of single stranded oligonucleotide and a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. 
     The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic, vaginal, rectal, intranasal, transdermal), oral or parenteral. Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection, or intrathecal or intraventricular administration. 
     The route and site of administration may be chosen to enhance targeting. For example, to target muscle cells, intramuscular injection into the muscles of interest would be a logical choice. Lung cells might be targeted by administering the single stranded oligonucleotide in aerosol form. The vascular endothelial cells could be targeted by coating a balloon catheter with the single stranded oligonucleotide and mechanically introducing the oligonucleotide. 
     Topical administration refers to the delivery to a subject by contacting the formulation directly to a surface of the subject. The most common form of topical delivery is to the skin, but a composition disclosed herein can also be directly applied to other surfaces of the body, e.g., to the eye, a mucous membrane, to surfaces of a body cavity or to an internal surface. As mentioned above, the most common topical delivery is to the skin. The term encompasses several routes of administration including, but not limited to, topical and transdermal. These modes of administration typically include penetration of the skin&#39;s permeability barrier and efficient delivery to the target tissue or stratum. Topical administration can be used as a means to penetrate the epidermis and dermis and ultimately achieve systemic delivery of the composition. Topical administration can also be used as a means to selectively deliver oligonucleotides to the epidermis or dermis of a subject, or to specific strata thereof, or to an underlying tissue. 
     Formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. 
     Transdermal delivery is a valuable route for the administration of lipid soluble therapeutics. The dermis is more permeable than the epidermis and therefore absorption is much more rapid through abraded, burned or denuded skin. Inflammation and other physiologic conditions that increase blood flow to the skin also enhance transdermal adsorption. Absorption via this route may be enhanced by the use of an oily vehicle (inunction) or through the use of one or more penetration enhancers. Other effective ways to deliver a composition disclosed herein via the transdermal route include hydration of the skin and the use of controlled release topical patches. The transdermal route provides a potentially effective means to deliver a composition disclosed herein for systemic and/or local therapy. In addition, iontophoresis (transfer of ionic solutes through biological membranes under the influence of an electric field), phonophoresis or sonophoresis (use of ultrasound to enhance the absorption of various therapeutic agents across biological membranes, notably the skin and the cornea), and optimization of vehicle characteristics relative to dose position and retention at the site of administration may be useful methods for enhancing the transport of topically applied compositions across skin and mucosal sites. 
     Both the oral and nasal membranes offer advantages over other routes of administration. For example, oligonucleotides administered through these membranes may have a rapid onset of action, provide therapeutic plasma levels, avoid first pass effect of hepatic metabolism, and avoid exposure of the oligonucleotides to the hostile gastrointestinal (GI) environment. Additional advantages include easy access to the membrane sites so that the oligonucleotide can be applied, localized and removed easily. 
     In oral delivery, compositions can be targeted to a surface of the oral cavity, e.g., to sublingual mucosa which includes the membrane of ventral surface of the tongue and the floor of the mouth or the buccal mucosa which constitutes the lining of the cheek. The sublingual mucosa is relatively permeable thus giving rapid absorption and acceptable bioavailability of many agents. Further, the sublingual mucosa is convenient, acceptable and easily accessible. 
     A pharmaceutical composition of single stranded oligonucleotide may also be administered to the buccal cavity of a human being by spraying into the cavity, without inhalation, from a metered dose spray dispenser, a mixed micellar pharmaceutical formulation as described above and a propellant. In one embodiment, the dispenser is first shaken prior to spraying the pharmaceutical formulation and propellant into the buccal cavity. 
     Compositions for oral administration include powders or granules, suspensions or solutions in water, syrups, slurries, emulsions, elixirs or non-aqueous media, tablets, capsules, lozenges, or troches. In the case of tablets, carriers that can be used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the nucleic acid compositions can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. 
     Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection, intrathecal or intraventricular administration. In some embodiments, parental administration involves administration directly to the site of disease (e.g. injection into a tumor). 
     Formulations for parenteral administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives. Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. 
     Any of the single stranded oligonucleotides described herein can be administered to ocular tissue. For example, the compositions can be applied to the surface of the eye or nearby tissue, e.g., the inside of the eyelid. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or poly(vinyl alcohol), preservatives such as sorbic acid, EDTA or benzylchronium chloride, and the usual quantities of diluents and/or carriers. The single stranded oligonucleotide can also be administered to the interior of the eye, and can be introduced by a needle or other delivery device which can introduce it to a selected area or structure. 
     Pulmonary delivery compositions can be delivered by inhalation by the patient of a dispersion so that the composition, preferably single stranded oligonucleotides, within the dispersion can reach the lung where it can be readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery can be effective both for systemic delivery and for localized delivery to treat diseases of the lungs. 
     Pulmonary delivery can be achieved by different approaches, including the use of nebulized, aerosolized, micellular and dry powder-based formulations. Delivery can be achieved with liquid nebulizers, aerosol-based inhalers, and dry powder dispersion devices. Metered-dose devices are preferred. One of the benefits of using an atomizer or inhaler is that the potential for contamination is minimized because the devices are self-contained. Dry powder dispersion devices, for example, deliver agents that may be readily formulated as dry powders. A single stranded oligonucleotide composition may be stably stored as lyophilized or spray-dried powders by itself or in combination with suitable powder carriers. The delivery of a composition for inhalation can be mediated by a dosing timing element which can include a timer, a dose counter, time measuring device, or a time indicator which when incorporated into the device enables dose tracking, compliance monitoring, and/or dose triggering to a patient during administration of the aerosol medicament. 
     The term “powder” means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration into the alveoli. Thus, the powder is said to be “respirable.” Preferably the average particle size is less than about 10 μm in diameter preferably with a relatively uniform spheroidal shape distribution. More preferably the diameter is less than about 7.5 μm and most preferably less than about 5.0 μm. Usually the particle size distribution is between about 0.1 μm and about 5 μm in diameter, particularly about 0.3 μm to about 5 μm. 
     The term “dry” means that the composition has a moisture content below about 10% by weight (% w) water, usually below about 5% w and preferably less it than about 3% w. A dry composition can be such that the particles are readily dispersible in an inhalation device to form an aerosol. 
     The types of pharmaceutical excipients that are useful as carrier include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two. 
     Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred. Pulmonary administration of a micellar single stranded oligonucleotide formulation may be achieved through metered dose spray devices with propellants such as tetrafluoroethane, heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and other non-CFC and CFC propellants. 
     Exemplary devices include devices which are introduced into the vasculature, e.g., devices inserted into the lumen of a vascular tissue, or which devices themselves form a part of the vasculature, including stents, catheters, heart valves, and other vascular devices. These devices, e.g., catheters or stents, can be placed in the vasculature of the lung, heart, or leg. 
     Other devices include non-vascular devices, e.g., devices implanted in the peritoneum, or in organ or glandular tissue, e.g., artificial organs. The device can release a therapeutic substance in addition to a single stranded oligonucleotide, e.g., a device can release insulin. 
     In one embodiment, unit doses or measured doses of a composition that includes single stranded oligonucleotide are dispensed by an implanted device. The device can include a sensor that monitors a parameter within a subject. For example, the device can include pump, e.g., and, optionally, associated electronics. 
     Tissue, e.g., cells or organs can be treated with a single stranded oligonucleotide, ex vivo and then administered or implanted in a subject. The tissue can be autologous, allogeneic, or xenogeneic tissue. E.g., tissue can be treated to reduce graft v. host disease. In other embodiments, the tissue is allogeneic and the tissue is treated to treat a disorder characterized by unwanted gene expression in that tissue. E.g., tissue, e.g., hematopoietic cells, e.g., bone marrow hematopoietic cells, can be treated to inhibit unwanted cell proliferation. Introduction of treated tissue, whether autologous or transplant, can be combined with other therapies. In some implementations, the single stranded oligonucleotide treated cells are insulated from other cells, e.g., by a semi-permeable porous barrier that prevents the cells from leaving the implant, but enables molecules from the body to reach the cells and molecules produced by the cells to enter the body. In one embodiment, the porous barrier is formed from alginate. 
     In one embodiment, a contraceptive device is coated with or contains a single stranded oligonucleotide. Exemplary devices include condoms, diaphragms, IUD (implantable uterine devices, sponges, vaginal sheaths, and birth control devices. 
     Dosage 
     In one aspect, the invention features a method of administering a single stranded oligonucleotide (e.g., as a compound or as a component of a composition) to a subject (e.g., a human subject). In one embodiment, the unit dose is between about 10 mg and 25 mg per kg of bodyweight. In one embodiment, the unit dose is between about 1 mg and 100 mg per kg of bodyweight. In one embodiment, the unit dose is between about 0.1 mg and 500 mg per kg of bodyweight. In some embodiments, the unit dose is more than 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 5, 10, 25, 50 or 100 mg per kg of bodyweight. 
     The defined amount can be an amount effective to treat or prevent a disease or condition, e.g., a disease or condition associated with the target gene. The unit dose, for example, can be administered by injection (e.g., intravenous or intramuscular), an inhaled dose, or a topical application. 
     In some embodiments, the unit dose is administered daily. In some embodiments, less frequently than once a day, e.g., less than every 2, 4, 8 or 30 days. In another embodiment, the unit dose is not administered with a frequency (e.g., not a regular frequency). For example, the unit dose may be administered a single time. In some embodiments, the unit dose is administered more than once a day, e.g., once an hour, two hours, four hours, eight hours, twelve hours, etc. 
     In one embodiment, a subject is administered an initial dose and one or more maintenance doses of a single stranded oligonucleotide. The maintenance dose or doses are generally lower than the initial dose, e.g., one-half less of the initial dose. A maintenance regimen can include treating the subject with a dose or doses ranging from 0.0001 to 100 mg/kg of body weight per day, e.g., 100, 10, 1, 0.1, 0.01, 0.001, or 0.0001 mg per kg of bodyweight per day. The maintenance doses may be administered no more than once every 1, 5, 10, or 30 days. Further, the treatment regimen may last for a period of time which will vary depending upon the nature of the particular disease, its severity and the overall condition of the patient. In some embodiments the dosage may be delivered no more than once per day, e.g., no more than once per 24, 36, 48, or more hours, e.g., no more than once for every 5 or 8 days. Following treatment, the patient can be monitored for changes in his condition and for alleviation of the symptoms of the disease state. The dosage of the oligonucleotide may either be increased in the event the patient does not respond significantly to current dosage levels, or the dose may be decreased if an alleviation of the symptoms of the disease state is observed, if the disease state has been ablated, or if undesired side-effects are observed. 
     The effective dose can be administered in a single dose or in two or more doses, as desired or considered appropriate under the specific circumstances. If desired to facilitate repeated or frequent infusions, implantation of a delivery device, e.g., a pump, semi-permanent stent (e.g., intravenous, intraperitoneal, intracisternal or intracapsular), or reservoir may be advisable. 
     In some embodiments, the oligonucleotide pharmaceutical composition includes a plurality of single stranded oligonucleotide species. In another embodiment, the single stranded oligonucleotide species has sequences that are non-overlapping and non-adjacent to another species with respect to a naturally occurring target sequence (e.g., a lancRNA). In another embodiment, the plurality of single stranded oligonucleotide species is specific for different lancRNAs. In another embodiment, the single stranded oligonucleotide is allele specific. In some cases, a patient is treated with a single stranded oligonucleotide in conjunction with other therapeutic modalities. 
     Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the compound of the invention is administered in maintenance doses, ranging from 0.0001 mg to 100 mg per kg of body weight. 
     The concentration of the single stranded oligonucleotide composition is an amount sufficient to be effective in treating or preventing a disorder or to regulate a physiological condition in humans. The concentration or amount of single stranded oligonucleotide administered will depend on the parameters determined for the agent and the method of administration, e.g. nasal, buccal, pulmonary. For example, nasal formulations may tend to require much lower concentrations of some ingredients in order to avoid irritation or burning of the nasal passages. It is sometimes desirable to dilute an oral formulation up to 10-100 times in order to provide a suitable nasal formulation. 
     Certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a single stranded oligonucleotide can include a single treatment or, preferably, can include a series of treatments. It will also be appreciated that the effective dosage of a single stranded oligonucleotide used for treatment may increase or decrease over the course of a particular treatment. For example, the subject can be monitored after administering a single stranded oligonucleotide composition. Based on information from the monitoring, an additional amount of the single stranded oligonucleotide composition can be administered. 
     Dosing is dependent on severity and responsiveness of the disease or condition to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of disease state is achieved. Optimal dosing schedules can be calculated from measurements of target gene expression levels in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual compounds, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. In some embodiments, the animal models include transgenic animals that express a human target gene. In another embodiment, the composition for testing includes a single stranded oligonucleotide that is complementary, at least in an internal region, to a sequence that is conserved between the target gene in the animal model and the target gene in a human. 
     In one embodiment, the administration of the single stranded oligonucleotide composition is parenteral, e.g. intravenous (e.g., as a bolus or as a diffusible infusion), intradermal, intraperitoneal, intramuscular, intrathecal, intraventricular, intracranial, subcutaneous, transmucosal, buccal, sublingual, endoscopic, rectal, oral, vaginal, topical, pulmonary, intranasal, urethral or ocular. Administration can be provided by the subject or by another person, e.g., a health care provider. The composition can be provided in measured doses or in a dispenser which delivers a metered dose. Selected modes of delivery are discussed in more detail below. 
     Kits 
     In certain aspects of the invention, kits are provided, comprising a container housing a composition comprising a single stranded oligonucleotide. In some embodiments, the composition is a pharmaceutical composition comprising a single stranded oligonucleotide and a pharmaceutically acceptable carrier. In some embodiments, the individual components of the pharmaceutical composition may be provided in one container. Alternatively, it may be desirable to provide the components of the pharmaceutical composition separately in two or more containers, e.g., one container for single stranded oligonucleotides, and at least another for a carrier compound. The kit may be packaged in a number of different configurations such as one or more containers in a single box. The different components can be combined, e.g., according to instructions provided with the kit. The components can be combined according to a method described herein, e.g., to prepare and administer a pharmaceutical composition. The kit can also include a delivery device. 
     The present invention is further illustrated by the following Examples, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated by reference. 
     EXAMPLES 
     The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. 
     Example 1. APOA1 and FXN lancRNA-Targeting Oligonucleotides 
     Oligo Design 
     Oligonucleotides were designed to target sense and antisense regions located within a 500 nucleotide window of the transcription start and end sites of APOA1 and FXN. The oligonucleotide sequence and modification (“formatted”) patterns are provided in Table 3 below. Table 4 provides a description of the nucleotide analogs, modifications and intranucleotide linkages used for certain oligonucleotides tested and described in Table 3. A map of each gene showing where each oligonucleotide binds is provided in  FIGS. 1 and 2 . 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Oligonucleotides test 
               
            
           
           
               
               
               
               
               
               
            
               
                 Oligo 
                   
                 Gene 
                 SEQ 
                   
                   
               
               
                 Name 
                 Organism 
                 Name 
                 ID NO 
                 Base Sequence 
                 Formatted Sequence 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 FXN- 
                 human 
                 FXN 
                 1 
                 CGCAGTAGCCGGCCT 
                 InaCs;omeGs;InaCs;omeAs;InaGs;omeU 
               
               
                 62 
                   
                   
                   
                   
                 s;InaAs;omeGs;InaCs;omeCs;InaGs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Gs;InaCs;omeCs;InaT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 2 
                 CCTGGCGTCACCCAG 
                 InaCs;omeCs;InaTs;omeGs;InaGs;omeC 
               
               
                 601 
                   
                   
                   
                   
                 s;InaGs;omeUs;InaCs;omeAs;InaCs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Cs;InaCs;omeAs;InaG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 3 
                 CCCAGCCCAGGCCCA 
                 InaCs;omeCs;InaCs;omeAs;InaGs;omeC 
               
               
                 602 
                   
                   
                   
                   
                 s;InaCs;omeCs;InaAs;omeGs;InaGs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Cs;InaCs;omeCs;InaA-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 4 
                 CCCAGACCCTCACCC 
                 InaCs;omeCs;InaCs;omeAs;InaGs;omeA 
               
               
                 603 
                   
                   
                   
                   
                 s;InaCs;omeCs;InaCs;omeUs;InaCs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 As;InaCs;omeCs;InaC-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 5 
                 TCCCGCGGCCGGCAG 
                 InaTs;omeCs;InaCs;omeCs;InaGs;omeCs 
               
               
                 604 
                   
                   
                   
                   
                 ;InaGs;omeGs;InaCs;omeCs;InaGs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Gs;InaCs;omeAs;InaG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 6 
                 AGAGTTGGCCCCACT 
                 InaAs;omeGs;InaAs;omeGs;InaTs;omeU 
               
               
                 605 
                   
                   
                   
                   
                 s;InaGs;omeGs;InaCs;omeCs;InaCs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Cs;InaAs;omeCs;InaT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 7 
                 AGCAGCTGGTCAACC 
                 dAs;InaGs;dCs;InaAs;dGs;InaCs;dTs;Ina 
               
               
                 606 
                   
                   
                   
                   
                 Gs;dGs;InaTs;dCs;InaAs;dAs;InaCs;dC- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 8 
                 TGCTCACTGTTCTAT 
                 dTs;InaGs;dCs;InaTs;dCs;InaAs;dCs;InaT 
               
               
                 607 
                   
                   
                   
                   
                 s;dGs;InaTs;dTs;InaCs;dTs;InaAs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 9 
                 CTCCAAATGAGACAC 
                 dCs;InaTs;dCs;InaCs;dAs;InaAs;dAs;InaT 
               
               
                 608 
                   
                   
                   
                   
                 s;dGs;InaAs;dGs;InaAs;dCs;InaAs;dC- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 10 
                 ATTAAAGGGTAGCCT 
                 dAs;InaTs;dTs;InaAs;dAs;InaAs;dGs;Ina 
               
               
                 609 
                   
                   
                   
                   
                 Gs;dGs;InaTs;dAs;InaGs;dCs;InaCs;dT- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 11 
                 ACAAATGTTTTCAGG 
                 dAs;InaCs;dAs;InaAs;dAs;InaTs;dGs;InaT 
               
               
                 610 
                   
                   
                   
                   
                 s;dTs;InaTs;dTs;InaCs;dAs;InaGs;dG-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 12 
                 CTTCTTTCAAAGTGT 
                 dCs;InaTs;dTs;InaCs;dTs;InaTs;dTs;InaCs 
               
               
                 611 
                   
                   
                   
                   
                 ;dAs;InaAs;dAs;InaGs;dTs;InaGs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 13 
                 TAATGTCTTATGCCT 
                 dTs;InaAs;dAs;InaTs;dGs;InaTs;dCs;InaT 
               
               
                 612 
                   
                   
                   
                   
                 s;dTs;InaAs;dTs;InaGs;dCs;InaCs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 14 
                 ATACCTGAATATAAC 
                 dAs;InaTs;dAs;InaCs;dCs;InaTs;dGs;InaA 
               
               
                 613 
                   
                   
                   
                   
                 s;dAs;InaTs;dAs;InaTs;dAs;InaAs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 15 
                 AACCTTTAAAAAAGC 
                 dAs;InaAs;dCs;InaCs;dTs;InaTs;dTs;InaA 
               
               
                 614 
                   
                   
                   
                   
                 s;dAs;InaAs;dAs;InaAs;dAs;InaGs;dC- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 16 
                 AAAATAATAAGAAGG 
                 dAs;InaAs;dAs;InaAs;dTs;InaAs;dAs;InaT 
               
               
                 615 
                   
                   
                   
                   
                 s;dAs;InaAs;dGs;InaAs;dAs;InaGs;dG- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 17 
                 AAAAATTCCAGGAGG 
                 dAs;InaAs;dAs;InaAs;dAs;InaTs;dTs;InaC 
               
               
                 616 
                   
                   
                   
                   
                 s;dCs;InaAs;dGs;InaGs;dAs;InaGs;dG- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 18 
                 GAAAATGAATTGTCT 
                 dGs;InaAs;dAs;InaAs;dAs;InaTs;dGs;Ina 
               
               
                 617 
                   
                   
                   
                   
                 As;dAs;InaTs;dTs;InaGs;dTs;InaCs;dT- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 19 
                 TCACTCTTCATTCTT 
                 dTs;InaCs;dAs;InaCs;dTs;InaCs;dTs;InaT 
               
               
                 618 
                   
                   
                   
                   
                 s;dCs;InaAs;dTs;InaTs;dCs;InaTs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 20 
                 TGAAGGATTTACTGC 
                 dTs;InaGs;dAs;InaAs;dGs;InaGs;dAs;Ina 
               
               
                 619 
                   
                   
                   
                   
                 Ts;dTs;InaTs;dAs;InaCs;dTs;InaGs;dC- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 21 
                 TTGGATTGTCGGAT 
                 dTs;InaTs;dGs;InaGs;dAs;InaTs;dTs;InaG 
               
               
                 620 
                   
                   
                   
                   
                 s;dTs;InaCs;dGs;InaGs;dAs;InaT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 22 
                 TTCCTCCCTCACATG 
                 dTs;InaTs;dCs;InaCs;dTs;InaCs;dCs;InaC 
               
               
                 621 
                   
                   
                   
                   
                 s;dTs;InaCs;dAs;InaCs;dAs;InaTs;dG-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 23 
                 ATACCCCTTATCTTT 
                 dAs;InaTs;dAs;InaCs;dCs;InaCs;dCs;InaT 
               
               
                 622 
                   
                   
                   
                   
                 s;dTs;InaAs;dTs;InaCs;dTs;InaTs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 24 
                 TATAATGTCTTATGC 
                 dTs;InaAs;dTs;InaAs;dAs;InaTs;dGs;InaT 
               
               
                 623 
                   
                   
                   
                   
                 s;dCs;InaTs;dTs;InaAs;dTs;InaGs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 25 
                 TGAGGACAGTTGGGC 
                 dTs;InaGs;dAs;InaGs;dGs;InaAs;dCs;Ina 
               
               
                 624 
                   
                   
                   
                   
                 As;dGs;InaTs;dTs;InaGs;dGs;InaGs;dC- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 26 
                 TATGTGTCACAGCTC 
                 dTs;InaAs;dTs;InaGs;dTs;InaGs;dTs;InaC 
               
               
                 625 
                   
                   
                   
                   
                 s;dAs;InaCs;dAs;InaGs;dCs;InaTs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 27 
                 TGTAGAAAGAATGTG 
                 dTs;InaGs;dTs;InaAs;dGs;InaAs;dAs;Ina 
               
               
                 626 
                   
                   
                   
                   
                 As;dGs;InaAs;dAs;InaTs;dGs;InaTs;dG- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 28 
                 TTGCCTCCTACCTTG 
                 dTs;InaTs;dGs;InaCs;dCs;InaTs;dCs;InaC 
               
               
                 627 
                   
                   
                   
                   
                 s;dTs;InaAs;dCs;InaCs;dTs;InaTs;dG-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 29 
                 CCCCCAAGTTCTGAT 
                 dCs;InaCs;dCs;InaCs;dCs;InaAs;dAs;InaG 
               
               
                 628 
                   
                   
                   
                   
                 s;dTs;InaTs;dCs;InaTs;dGs;InaAs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 30 
                 ATGCTTGATGCCCAG 
                 dAs;InaTs;dGs;InaCs;dTs;InaTs;dGs;InaA 
               
               
                 629 
                   
                   
                   
                   
                 s;dTs;InaGs;dCs;InaCs;dCs;InaAs;dG- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 31 
                 CCCCGTTTTAAGGAC 
                 dCs;InaCs;dCs;InaCs;dGs;InaTs;dTs;InaT 
               
               
                 630 
                   
                   
                   
                   
                 s;dTs;InaAs;dAs;InaGs;dGs;InaAs;dC- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 32 
                 ATTAAAAGCTATCAG 
                 dAs;InaTs;dTs;InaAs;dAs;InaAs;dAs;InaG 
               
               
                 631 
                   
                   
                   
                   
                 s;dCs;InaTs;dAs;InaTs;dCs;InaAs;dG-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 33 
                 GCCAAGACCCCAGCT 
                 dGs;InaCs;dCs;InaAs;dAs;InaGs;dAs;Ina 
               
               
                 632 
                   
                   
                   
                   
                 Cs;dCs;InaCs;dCs;InaAs;dGs;InaCs;dT- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 34 
                 TCATTATGCAGCTGA 
                 dTs;InaCs;dAs;InaTs;dTs;InaAs;dTs;InaG 
               
               
                 633 
                   
                   
                   
                   
                 s;dCs;InaAs;dGs;InaCs;dTs;InaGs;dA- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 35 
                 GGTCTGTTTTTTGTT 
                 dGs;InaGs;dTs;InaCs;dTs;InaGs;dTs;InaT 
               
               
                 634 
                   
                   
                   
                   
                 s;dTs;InaTs;dTs;InaTs;dGs;InaTs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 36 
                 GTTGTTGTTGTTTAT 
                 dGs;InaTs;dTs;InaGs;dTs;InaTs;dGs;InaT 
               
               
                 635 
                   
                   
                   
                   
                 s;dTs;InaGs;dTs;InaTs;dTs;InaAs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 37 
                 GCAGAGCTCACTAAA 
                 dGs;InaCs;dAs;InaGs;dAs;InaGs;dCs;Ina 
               
               
                 636 
                   
                   
                   
                   
                 Ts;dCs;InaAs;dCs;InaTs;dAs;InaAs;dA- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 38 
                 GCCTTAAAAACCAAA 
                 dGs;InaCs;dCs;InaTs;dTs;InaAs;dAs;InaA 
               
               
                 637 
                   
                   
                   
                   
                 s;dAs;InaAs;dCs;InaCs;dAs;InaAs;dA- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 39 
                 CTGGACTTGTCTTCC 
                 dCs;InaTs;dGs;InaGs;dAs;InaCs;dTs;InaT 
               
               
                 638 
                   
                   
                   
                   
                 s;dGs;InaTs;dCs;InaTs;dTs;InaCs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 40 
                 CAGGACATTAAAATT 
                 dCs;InaAs;dGs;InaGs;dAs;InaCs;dAs;Ina 
               
               
                 640 
                   
                   
                   
                   
                 Ts;dTs;InaAs;dAs;InaAs;dAs;InaTs;dT- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 41 
                 CATGCAAAGTTATGC 
                 dCs;InaAs;dTs;InaGs;dCs;InaAs;dAs;InaA 
               
               
                 641 
                   
                   
                   
                   
                 s;dGs;InaTs;dTs;InaAs;dTs;InaGs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 42 
                 AAGTGCAGTAGGCCA 
                 dAs;InaAs;dGs;InaTs;dGs;InaCs;dAs;Ina 
               
               
                 642 
                   
                   
                   
                   
                 Gs;dTs;InaAs;dGs;InaGs;dCs;InaCs;dA- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 43 
                 GTGCCAGTGAGAAAA 
                 dGs;InaTs;dGs;InaCs;dCs;InaAs;dGs;Ina 
               
               
                 643 
                   
                   
                   
                   
                 Ts;dGs;InaAs;dGs;InaAs;dAs;InaAs;dA- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 44 
                 TAAATAACATCATAC 
                 dTs;InaAs;dAs;InaAs;dTs;InaAs;dAs;InaC 
               
               
                 644 
                   
                   
                   
                   
                 s;dAs;InaTs;dCs;InaAs;dTs;InaAs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 45 
                 ATGTTTGTATGTGTT 
                 dAs;InaTs;dGs;InaTs;dTs;InaTs;dGs;InaT 
               
               
                 645 
                   
                   
                   
                   
                 s;dAs;InaTs;dGs;InaTs;dGs;InaTs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 46 
                 AATCTATAAAATGGA 
                 dAs;InaAs;dTs;InaCs;dTs;InaAs;dTs;InaA 
               
               
                 646 
                   
                   
                   
                   
                 s;dAs;InaAs;dAs;InaTs;dGs;InaGs;dA- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 47 
                 CAGTTTGCATTAAAT 
                 dCs;InaAs;dGs;InaTs;dTs;InaTs;dGs;InaC 
               
               
                 647 
                   
                   
                   
                   
                 s;dAs;InaTs;dTs;InaAs;dAs;InaAs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 48 
                 TATAGGTTTACAATA 
                 dTs;InaAs;dTs;InaAs;dGs;InaGs;dTs;InaT 
               
               
                 648 
                   
                   
                   
                   
                 s;dTs;InaAs;dCs;InaAs;dAs;InaTs;dA-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 49 
                 GTTATAATTATATGT 
                 dGs;InaTs;dTs;InaAs;dTs;InaAs;dAs;InaT 
               
               
                 649 
                   
                   
                   
                   
                 s;dTs;InaAs;dTs;InaAs;dTs;InaGs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 50 
                 TTAAGATAGTTGTTC 
                 dTs;InaTs;dAs;InaAs;dGs;InaAs;dTs;InaA 
               
               
                 650 
                   
                   
                   
                   
                 s;dGs;InaTs;dTs;InaGs;dTs;InaTs;dC-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 51 
                 AATAAACTCTAAATA 
                 dAs;InaAs;dTs;InaAs;dAs;InaAs;dCs;InaT 
               
               
                 651 
                   
                   
                   
                   
                 s;dCs;InaTs;dAs;InaAs;dAs;InaTs;dA-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 52 
                 ACCCCAACTCCAAGA 
                 dAs;InaCs;dCs;InaCs;dCs;InaAs;dAs;InaC 
               
               
                 652 
                   
                   
                   
                   
                 s;dTs;InaCs;dCs;InaAs;dAs;InaGs;dA-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 53 
                 GTGTTAGCAAGAAAT 
                 dGs;InaTs;dGs;InaTs;dTs;InaAs;dGs;InaC 
               
               
                 653 
                   
                   
                   
                   
                 s;dAs;InaAs;dGs;InaAs;dAs;InaAs;dT- 
               
               
                 m02 
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 54 
                 TCCAAAATGGAATA 
                 InaTs;omeCs;InaCs;omeAs;InaAs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 G 
                 eAs;InaAs;omeTs;InaGs;omeGs;InaA 
               
               
                 s-26 
                   
                   
                   
                   
                 s;omeAs;InaTs;omeAs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 55 
                 TTTCCAAAATGGAA 
                 InaTs;omeTs;InaTs;omeCs;InaCs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 T 
                 eAs;InaAs;omeAs;InaAs;omeTs;InaG 
               
               
                 s-27 
                   
                   
                   
                   
                 s;omeGs;InaAs;omeAs;InaT-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 56 
                 ACCTTTCCAAAATG 
                 InaAs;omeCs;InaCs;omeTs;InaTs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 G 
                 eTs;InaCs;omeCs;InaAs;omeAs;InaA 
               
               
                 s-28 
                   
                   
                   
                   
                 s;omeAs;InaTs;omeGs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 57 
                 AACCTTTCCAAAAT 
                 InaAs;omeAs;InaCs;omeCs;InaTs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 G 
                 eTs;InaTs;omeCs;InaCs;omeAs;InaA 
               
               
                 s-29 
                   
                   
                   
                   
                 s;omeAs;InaAs;omeTs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 58 
                 ACAATAAACCTTTC 
                 InaAs;omeCs;InaAs;omeAs;InaTs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 C 
                 meAs;InaAs;omeAs;InaCs;omeCs;In 
               
               
                 s-30 
                   
                   
                   
                   
                 aTs;omeTs;InaTs;omeCs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 59 
                 GGTGCCCGCTTCCA 
                 InaGs;omeGs;InaTs;omeGs;InaCs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 C 
                 meCs;InaCs;omeGs;InaCs;omeTs;Ina 
               
               
                 s-31 
                   
                   
                   
                   
                 Ts;omeCs;InaCs;omeAs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 60 
                 TCCACTCCCCACCC 
                 InaTs;omeCs;InaCs;omeAs;InaCs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 C 
                 eTs;InaCs;omeCs;InaCs;omeCs;InaA 
               
               
                 s-32 
                   
                   
                   
                   
                 s;omeCs;InaCs;omeCs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 61 
                 ACCCCCGCATTGGC 
                 InaAs;omeCs;InaCs;omeCs;InaCs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 T 
                 eCs;InaGs;omeCs;InaAs;omeTs;InaT 
               
               
                 s-33 
                   
                   
                   
                   
                 s;omeGs;InaGs;omeCs;InaT-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 62 
                 TGGCTTTCTTACAA 
                 InaTs;omeGs;InaGs;omeCs;InaTs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 T 
                 meTs;InaTs;omeCs;InaTs;omeTs;Ina 
               
               
                 s-34 
                   
                   
                   
                   
                 As;omeCs;InaAs;omeAs;InaT-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 63 
                 GGAATAGCTTCTTT 
                 InaGs;omeGs;InaAs;omeAs;InaTs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 C 
                 meAs;InaGs;omeCs;InaTs;omeTs;Ina 
               
               
                 s-35 
                   
                   
                   
                   
                 Cs;omeTs;InaTs;omeTs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 64 
                 CTTTCTTTGGGGGA 
                 InaCs;omeTs;InaTs;omeTs;InaCs;om 
               
               
                 1_mu 
                   
                   
                   
                 C 
                 eTs;InaTs;omeTs;InaGs;omeGs;InaG 
               
               
                 s-36 
                   
                 1 
                   
                   
                 s;omeGs;InaGs;omeAs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 65 
                 CACCCAGACTGTCG 
                 InaCs;omeAs;InaCs;omeCs;InaCs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 G 
                 eAs;InaGs;omeAs;InaCs;omeTs;InaG 
               
               
                 s-37 
                   
                   
                   
                   
                 s;omeTs;InaCs;omeGs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 66 
                 CAGGGCCAGGCTG 
                 InaCs;omeAs;InaGs;omeGs;InaGs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 AG 
                 meCs;InaCs;omeAs;InaGs;omeGs;In 
               
               
                 s-38 
                   
                   
                   
                   
                 aCs;omeTs;InaGs;omeAs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 67 
                 GCTGATCCTTGAAC 
                 InaGs;omeCs;InaTs;omeGs;InaAs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 T 
                 meTs;InaCs;omeCs;InaTs;omeTs;Ina 
               
               
                 s-39 
                   
                   
                   
                   
                 Gs;omeAs;InaAs;omeCs;InaT-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 68 
                 AGACTGTCGGAGA 
                 InaAs;omeGs;InaAs;omeCs;InaTs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 GC 
                 meGs;InaTs;omeCs;InaGs;omeGs;In 
               
               
                 s-40 
                   
                   
                   
                   
                 aAs;omeGs;InaAs;omeGs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 69 
                 TGTCGGAGAGCTC 
                 InaTs;omeGs;InaTs;omeCs;InaGs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 CG 
                 meGs;InaAs;omeGs;InaAs;omeGs;In 
               
               
                 s-41 
                   
                   
                   
                   
                 aCs;omeTs;InaCs;omeCs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 70 
                 GCTGGACACCCAG 
                 InaGs;omeCs;InaTs;omeGs;InaGs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 AC 
                 meAs;InaCs;omeAs;InaCs;omeCs;In 
               
               
                 s-42 
                   
                   
                   
                   
                 aCs;omeAs;InaGs;omeAs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 71 
                 GAAGAGCTGGACA 
                 InaGs;omeAs;InaAs;omeGs;InaAs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 CC 
                 meGs;InaCs;omeTs;InaGs;omeGs;In 
               
               
                 s-43 
                   
                   
                   
                   
                 aAs;omeCs;InaAs;omeCs;InaC-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 72 
                 GGGAAGAAGAGCT 
                 InaGs;omeGs;InaGs;omeAs;InaAs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 GG 
                 meGs;InaAs;omeAs;InaGs;omeAs;In 
               
               
                 s-44 
                   
                   
                   
                   
                 aGs;omeCs;InaTs;omeGs;InaG-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 73 
                 GACCAGGGAAGAA 
                 InaGs;omeAs;InaCs;omeCs;InaAs;o 
               
               
                 1_mu 
                   
                 1 
                   
                 GA 
                 meGs;InaGs;omeGs;InaAs;omeAs;In 
               
               
                 s-45 
                   
                   
                   
                   
                 aGs;omeAs;InaAs;omeGs;InaA-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 Apoa 
                 mouse 
                 Apoa 
                 74 
                 CACATATATAGACC 
                 InaCs;omeAs;InaCs;omeAs;InaTs;om 
               
               
                 1_mu 
                   
                 1 
                   
                 A 
                 eAs;InaTs;omeAs;InaTs;omeAs;InaG 
               
               
                 s-46 
                   
                   
                   
                   
                 s;omeAs;InaCs;omeCs;InaA-Sup 
               
               
                 m01 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 75 
                 GTCTCCCTTGGGTC 
                 InaGs;omeUs;InaCs;omeUs;InaCs;o 
               
               
                 800 
                   
                   
                   
                 A 
                 meCs;InaCs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeGs;InaTs;omeCs;InaA-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 76 
                 TGCGGCCAGTGGC 
                 InaTs;omeGs;InaCs;omeGs;InaGs;o 
               
               
                 801 
                   
                   
                   
                 CA 
                 meCs;InaCs;omeAs;InaGs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeGs;InaCs;omeCs;InaA-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 77 
                 CACCAGGGGTCGC 
                 InaCs;omeAs;InaCs;omeCs;InaAs;o 
               
               
                 802 
                   
                   
                   
                 CG 
                 meGs;deazaGs;omeGs;InaGs;omeU 
               
               
                 m01 
                   
                   
                   
                   
                 s;InaCs;omeGs;InaCs;omeCs;InaG- 
               
               
                   
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 78 
                 CAGCGCTGGAGGG 
                 InaCs;omeAs;InaGs;omeCs;InaGs;o 
               
               
                 803 
                   
                   
                   
                 CG 
                 meCs;InaTs;omeGs;InaGs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeGs;deazaGs;omeCs;InaG- 
               
               
                   
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 79 
                 CTGGAGGGCGGAG 
                 InaCs;omeUs;InaGs;omeGs;InaAs;o 
               
               
                 804 
                   
                   
                   
                 CG 
                 meGs;deazaGs;omeGs;InaCs;omeGs 
               
               
                 m01 
                   
                   
                   
                   
                 ;InaGs;omeAs;InaGs;omeCs;InaG- 
               
               
                   
                   
                   
                   
                   
                 Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 80 
                 GTCTCCCTTGGGTC 
                 InaGs;InaTs;InaCs;dTs;dCs;dCs;dCs;d 
               
               
                 800 
                   
                   
                   
                 A 
                 Ts;dTs;dGs;dGs;dGs;InaTs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 81 
                 TGCGGCCAGTGGC 
                 InaTs;InaGs;InaCs;dGs;dGs;dCs;dCs; 
               
               
                 801 
                   
                   
                   
                 CA 
                 dAs;dGs;dTs;dGs;dGs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 82 
                 CACCAGGGGTCGC 
                 InaCs;InaAs;InaCs;dCs;dAs;dGs;dGs; 
               
               
                 802 
                   
                   
                   
                 CG 
                 dGs;dGs;dTs;dCs;dGs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 83 
                 CAGCGCTGGAGGG 
                 InaCs;InaAs;InaGs;dCs;dGs;dCs;dTs; 
               
               
                 803 
                   
                   
                   
                 CG 
                 dGs;dGs;dAs;dGs;dGs;InaGs;InaCs;1 
               
               
                 m08 
                   
                   
                   
                   
                 naG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 84 
                 CTGGAGGGCGGAG 
                 InaCs;InaTs;InaGs;dGs;dAs;dGs;dGs; 
               
               
                 804 
                   
                   
                   
                 CG 
                 dGs;dCs;dGs;dGs;dAs;InaGs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 85 
                 AACTGCTGTAAACC 
                 InaAs;InaAs;InaCs;dTs;dGs;dCs;dTs; 
               
               
                 805 
                   
                   
                   
                 C 
                 dGs;dTs;dAs;dAs;dAs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 86 
                 ATACCGGCGGCCA 
                 InaAs;InaTs;InaAs;dCs;dCs;dGs;dGs; 
               
               
                 806 
                   
                   
                   
                 AG 
                 dCs;dGs;dGs;dCs;dCs;InaAs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 87 
                 CAGCCTCAATTTGT 
                 InaCs;InaAs;InaGs;dCs;dCs;dTs;dCs; 
               
               
                 807 
                   
                   
                   
                 G 
                 dAs;dAs;dTs;dTs;dTs;InaGs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 88 
                 CATGCACCCACTTC 
                 InaCs;InaAs;InaTs;dGs;dCs;dAs;dCs; 
               
               
                 808 
                   
                   
                   
                 C 
                 dCs;dCs;dAs;dCs;dTs;InaTs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 89 
                 CAGCAAGACAGCA 
                 InaCs;InaAs;InaGs;dCs;dAs;dAs;dGs; 
               
               
                 809 
                   
                   
                   
                 GC 
                 dAs;dCs;dAs;dGs;dCs;InaAs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 90 
                 TCCCAAGTTCCTCC 
                 InaTs;InaCs;InaCs;dCs;dAs;dAs;dGs; 
               
               
                 810 
                   
                   
                   
                 T 
                 dTs;dTs;dCs;dCs;dTs;InaCs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 91 
                 GTTTAGAATTTTAG 
                 InaGs;InaTs;InaTs;dTs;dAs;dGs;dAs; 
               
               
                 811 
                   
                   
                   
                 A 
                 dAs;dTs;dTs;dTs;dTs;InaAs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 92 
                 GGCTGCAGTCTCCC 
                 InaGs;InaGs;InaCs;dTs;dGs;dCs;dAs; 
               
               
                 812 
                   
                   
                   
                 T 
                 dGs;dTs;dCs;dTs;dCs;InaCs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 93 
                 TCCTGGTTGCACTC 
                 InaTs;InaCs;InaCs;dTs;dGs;dGs;dTs; 
               
               
                 588 
                   
                   
                   
                 C 
                 dTs;dGs;dCs;dAs;dCs;InaTs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 94 
                 AGTTCTTCCTGAGG 
                 InaAs;InaGs;InaTs;dTs;dCs;dTs;dTs;d 
               
               
                 593 
                   
                   
                   
                 T 
                 Cs;dCs;dTs;dGs;dAs;InaGs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 95 
                 CTAACCTCTAGCTG 
                 InaCs;InaTs;InaAs;dAs;dCs;dCs;dTs;d 
               
               
                 40 
                   
                   
                   
                 C 
                 Cs;dTs;dAs;dGs;dCs;InaTs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 96 
                 CACAGAAGAGTGC 
                 InaCs;InaAs;InaCs;dAs;dGs;dAs;dAs; 
               
               
                 816 
                   
                   
                   
                 CT 
                 dGs;dAs;dGs;dTs;dGs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 97 
                 GCCAGTGGCCACC 
                 InaGs;InaCs;InaCs;dAs;dGs;dTs;dGs; 
               
               
                 817 
                   
                   
                   
                 AG 
                 dGs;dCs;dCs;dAs;dCs;InaCs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 98 
                 GCAGCACCCAGCG 
                 InaGs;InaCs;InaAs;dGs;dCs;dAs;dCs; 
               
               
                 818 
                   
                   
                   
                 CT 
                 dCs;dCs;dAs;dGs;dCs;InaGs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 99 
                 GAGCAGCATGTGG 
                 InaGs;InaAs;InaGs;dCs;dAs;dGs;dCs; 
               
               
                 819 
                   
                   
                   
                 AC 
                 dAs;dTs;dGs;dTs;dGs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 100 
                 TCTCCCACTCAACA 
                 InaTs;InaCs;InaTs;dCs;dCs;dCs;dAs;d 
               
               
                 820 
                   
                   
                   
                 C 
                 Cs;dTs;dCs;dAs;dAs;InaCs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 101 
                 TCACACCTGTTAGT 
                 InaTs;InaCs;InaAs;dCs;dAs;dCs;dCs; 
               
               
                 821 
                   
                   
                   
                 T 
                 dTs;dGs;dTs;dTs;dAs;InaGs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 102 
                 TTCCTCTTGACACTT 
                 InaTs;InaTs;InaCs;dCs;dTs;dCs;dTs;d 
               
               
                 822 
                   
                   
                   
                   
                 Ts;dGs;dAs;dCs;dAs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 103 
                 GTCATTTAGCATCC 
                 InaGs;InaTs;InaCs;dAs;dTs;dTs;dTs;d 
               
               
                 823 
                   
                   
                   
                 T 
                 As;dGs;dCs;dAs;dTs;InaCs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 104 
                 AAGTATGTAAACAT 
                 InaAs;InaAs;InaGs;dTs;dAs;dTs;dGs; 
               
               
                 824 
                   
                   
                   
                 G 
                 dTs;dAs;dAs;dAs;dCs;InaAs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 105 
                 CACGATTCACAAAG 
                 InaCs;InaAs;InaCs;dGs;dAs;dTs;dTs; 
               
               
                 825 
                   
                   
                   
                 T 
                 dCs;dAs;dCs;dAs;dAs;InaAs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 106 
                 GGCTTTGGAAGAA 
                 InaGs;InaGs;InaCs;dTs;dTs;dTs;dGs; 
               
               
                 826 
                   
                   
                   
                 CT 
                 dGs;dAs;dAs;dGs;dAs;InaAs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 107 
                 TTAGTACCTTCCCA 
                 InaTs;InaTs;InaAs;dGs;dTs;dAs;dCs; 
               
               
                 827 
                   
                   
                   
                 T 
                 dCs;dTs;dTs;dCs;dCs;InaCs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 108 
                 GTCTCCCTTGGGTC 
                 InaGs;omeUs;InaCs;omeUs;InaCs;o 
               
               
                 800 
                   
                   
                   
                 A 
                 meCs;InaCs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeGs;InaTs;omeCs;InaA-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 109 
                 CGCTCCGCCCTCCAG 
                 dCs;InaGs;dCs;InaTs;dCs;InaCs;dGs;InaC 
               
               
                 375 
                   
                   
                   
                   
                 s;dCs;InaCs;dTs;InaCs;dCs;InaAs;dG-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 110 
                 ATTATTTTGCTTTTT 
                 dAs;InaTs;dTs;InaAs;dTs;InaTs;dTs;InaTs 
               
               
                 390 
                   
                   
                   
                   
                 ;dGs;InaCs;dTs;InaTs;dTs;InaTs;dT-Sup 
               
               
                 m02 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 111 
                 AGGCCACGGCGGCC 
                 InaAs;omeGs;InaGs;omeCs;InaCs;omeA 
               
               
                 577 
                   
                   
                   
                 GCA 
                 s;InaCs;omeGs;InaGs;omeCs;InaGs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Gs;InaCs;omeCs;InaGs;omeCs;InaA-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 112 
                 CATCGATGTCGGTGC 
                 InaCs;omeAs;InaTs;omeCs;InaGs;omeA 
               
               
                 578 
                   
                   
                   
                 GC 
                 s;InaTs;omeGs;InaTs;omeCs;InaGs;ome 
               
               
                 m01 
                   
                   
                   
                   
                 Gs;InaTs;omeGs;InaCs;omeGs;InaC-Sup 
               
               
                   
               
               
                 FXN- 
                 human 
                 FXN 
                 113 
                 ACACATAGCCCAACT 
                 InaAs;InaCs;InaAs;dCs;dAs;dTs;dAs;dGs; 
               
               
                 695 
                   
                   
                   
                   
                 dCs;dCs;dCs;dAs;InaAs;InaCs;InaT-Sup 
               
               
                 m08 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 114 
                 CTCAGACCACCGCC 
                 InaCs;omeUs;InaCs;omeAs;InaGs;o 
               
               
                 17 
                   
                   
                   
                 T 
                 meAs;InaCs;omeCs;InaAs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeGs;InaCs;omeCs;InaT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 115 
                 CCACCGCCTCCCCT 
                 InaCs;omeCs;InaAs;omeCs;InaCs;om 
               
               
                 18 
                   
                   
                   
                 G 
                 eGs;InaCs;omeCs;InaTs;omeCs;InaC 
               
               
                 m01 
                   
                   
                   
                   
                 s;omeCs;InaCs;omeUs;InaG-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 116 
                 CAGGCCCCATAAAA 
                 InaCs;omeAs;InaGs;omeGs;InaCs;o 
               
               
                 19 
                   
                   
                   
                 G 
                 meCs;InaCs;omeCs;InaAs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeAs;InaAs;omeAs;InaG-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 117 
                 CATAAAAGCGACT 
                 InaCs;omeAs;InaTs;omeAs;InaAs;o 
               
               
                 20 
                   
                   
                   
                 GT 
                 meAs;InaAs;omeGs;InaCs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeCs;InaTs;omeGs;InaT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 118 
                 ACTGTCACTCGGTC 
                 InaAs;omeCs;InaTs;omeGs;InaTs;om 
               
               
                 21 
                   
                   
                   
                 C 
                 eCs;InaAs;omeCs;InaTs;omeCs;InaG 
               
               
                 m01 
                   
                   
                   
                   
                 s;omeGs;InaTs;omeCs;InaC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 119 
                 ACTCGGTCCCAGAC 
                 InaAs;omeCs;InaTs;omeCs;InaGs;o 
               
               
                 22 
                   
                   
                   
                 A 
                 meGs;InaTs;omeCs;InaCs;omeCs;Ina 
               
               
                 m01 
                   
                   
                   
                   
                 As;omeGs;InaAs;omeCs;InaA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 120 
                 AGACACCAGAGCA 
                 InaAs;omeGs;InaAs;omeCs;InaAs;o 
               
               
                 23 
                   
                   
                   
                 AG 
                 meCs;InaCs;omeAs;InaGs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeCs;InaAs;omeAs;InaG-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 121 
                 GAGCAAGCTCAAG 
                 InaGs;omeAs;InaGs;omeCs;InaAs;o 
               
               
                 24 
                   
                   
                   
                 AC 
                 meAs;InaGs;omeCs;InaTs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeAs;InaGs;omeAs;InaC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 122 
                 GCAAGACGTAGAA 
                 InaGs;omeCs;InaAs;omeAs;InaGs;o 
               
               
                 25 
                   
                   
                   
                 CC 
                 meAs;InaCs;omeGs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaAs;omeCs;InaC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 123 
                 AGACGTAGAACCT 
                 InaAs;omeGs;InaAs;omeCs;InaGs;o 
               
               
                 26 
                   
                   
                   
                 AC 
                 meUs;InaAs;omeGs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaTs;omeAs;InaC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 124 
                 AGAACCTACCTGCC 
                 InaAs;omeGs;InaAs;omeAs;InaCs;o 
               
               
                 27 
                   
                   
                   
                 C 
                 meCs;InaTs;omeAs;InaCs;omeCs;Ina 
               
               
                 m01 
                   
                   
                   
                   
                 Ts;omeGs;InaCs;omeCs;InaC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 125 
                 ACATAGGTCTTGGA 
                 InaAs;omeCs;InaAs;omeUs;InaAs;o 
               
               
                 28 
                   
                   
                   
                 A 
                 meGs;InaGs;omeUs;InaCs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeGs;InaGs;omeAs;InaA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 126 
                 AGGTCTTGGAATA 
                 InaAs;omeGs;InaGs;omeUs;InaCs;o 
               
               
                 29 
                   
                   
                   
                 AA 
                 meUs;InaTs;omeGs;InaGs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeUs;InaAs;omeAs;InaA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 127 
                 TGGAATAAAATGG 
                 InaTs;omeGs;InaGs;omeAs;InaAs;o 
               
               
                 30 
                   
                   
                   
                 CT 
                 meUs;InaAs;omeAs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeGs;InaGs;omeCs;InaT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 128 
                 TGGCTGGTTCTTTT 
                 InaTs;omeGs;InaGs;omeCs;InaTs;o 
               
               
                 31 
                   
                   
                   
                 G 
                 meGs;InaGs;omeUs;InaTs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeUs;InaTs;omeUs;InaG-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 129 
                 GTTTTCCAAACCAG 
                 InaGs;omeUs;InaTs;omeUs;InaTs;o 
               
               
                 32 
                   
                   
                   
                 A 
                 meCs;InaCs;omeAs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaAs;omeGs;InaA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 130 
                 ACCAGAGTGTCTGT 
                 InaAs;omeCs;InaCs;omeAs;InaGs;o 
               
               
                 33 
                   
                   
                   
                 T 
                 meAs;InaGs;omeUs;InaGs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaGs;omeUs;InaT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 131 
                 AGTGTCTGTTGTCC 
                 InaAs;omeGs;InaTs;omeGs;InaTs;o 
               
               
                 34 
                   
                   
                   
                 T 
                 meCs;InaTs;omeGs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeUs;InaCs;omeCs;InaT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 132 
                 GTTGTCCTTTCTCTC 
                 InaGs;omeUs;InaTs;omeGs;InaTs;o 
               
               
                 35 
                   
                   
                   
                   
                 meCs;InaCs;omeUs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaCs;omeUs;InaC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 133 
                 CTTTCTCTCTGCCG 
                 InaCs;omeUs;InaTs;omeUs;InaCs;o 
               
               
                 36 
                   
                   
                   
                 A 
                 meUs;InaCs;omeUs;InaCs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeCs;InaCs;omeGs;InaA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 134 
                 CTGCCGAGTGTCTG 
                 InaCs;omeUs;InaGs;omeCs;InaCs;o 
               
               
                 37 
                   
                   
                   
                 T 
                 meGs;InaAs;omeGs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeCs;InaTs;omeGs;InaT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 135 
                 CTCAGACCACCGCC 
                 InaCs;InaTs;InaCs;dAs;dGs;dAs;dCs; 
               
               
                 17 
                   
                   
                   
                 T 
                 dCs;dAs;dCs;dCs;dGs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 136 
                 CCACCGCCTCCCCT 
                 InaCs;InaCs;InaAs;dCs;dCs;dGs;dCs; 
               
               
                 18 
                   
                   
                   
                   
                 dCs;dTs;dCs;dCs;dCs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 137 
                 CAGGCCCCATAAAA 
                 InaCs;InaAs;InaGs;dGs;dCs;dCs;dCs; 
               
               
                 19 
                   
                   
                   
                 G 
                 dCs;dAs;dTs;dAs;dAs;InaAs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 138 
                 CATAAAAGCGACT 
                 InaCs;InaAs;InaTs;dAs;dAs;dAs;dAs; 
               
               
                 20 
                   
                   
                   
                 GT 
                 dGs;dCs;dGs;dAs;dCs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 139 
                 ACTGTCACTCGGTC 
                 InaAs;InaCs;InaTs;dGs;dTs;dCs;dAs; 
               
               
                 21 
                   
                   
                   
                 C 
                 dCs;dTs;dCs;dGs;dGs;InaTs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 140 
                 ACTCGGTCCCAGAC 
                 InaAs;InaCs;InaTs;dCs;dGs;dGs;dTs; 
               
               
                 22 
                   
                   
                   
                 A 
                 dCs;dCs;dCs;dAs;dGs;InaAs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 141 
                 AGACACCAGAGCA 
                 InaAs;InaGs;InaAs;dCs;dAs;dCs;dCs; 
               
               
                 23 
                   
                   
                   
                 AG 
                 dAs;dGs;dAs;dGs;dCs;InaAs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 142 
                 GAGCAAGCTCAAG 
                 InaGs;InaAs;InaGs;dCs;dAs;dAs;dGs; 
               
               
                 24 
                   
                   
                   
                 AC 
                 dCs;dTs;dCs;dAs;dAs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 143 
                 GCAAGACGTAGAA 
                 InaGs;InaCs;InaAs;dAs;dGs;dAs;dCs; 
               
               
                 25 
                   
                   
                   
                 CC 
                 dGs;dTs;dAs;dGs;dAs;InaAs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 144 
                 AGACGTAGAACCT 
                 InaAs;InaGs;InaAs;dCs;dGs;dTs;dAs; 
               
               
                 26 
                   
                   
                   
                 AC 
                 dGs;dAs;dAs;dCs;dCs;InaTs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 145 
                 AGAACCTACCTGCC 
                 InaAs;InaGs;InaAs;dAs;dCs;dCs;dTs; 
               
               
                 27 
                   
                   
                   
                 C 
                 dAs;dCs;dCs;dTs;dGs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 HAMP 
                 human- 
                 HAMP 
                 146 
                 ACATAGGTCTTGGA 
                 InaAs;InaCs;InaAs;dTs;dAs;dGs;dGs; 
               
               
                 28 
                   
                   
                   
                 A 
                 dTs;dCs;dTs;dTs;dGs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 147 
                 AGGTCTTGGAATA 
                 InaAs;InaGs;InaGs;dTs;dCs;dTs;dTs; 
               
               
                 29 
                   
                   
                   
                 AA 
                 dGs;dGs;dAs;dAs;dTs;InaAs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 148 
                 TGGAATAAAATGG 
                 InaTs;InaGs;InaGs;dAs;dAs;dTs;dAs; 
               
               
                 30 
                   
                   
                   
                 CT 
                 dAs;dAs;dAs;dTs;dGs;InaGs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 149 
                 TGGCTGGTTCTTTT 
                 InaTs;InaGs;InaGs;dCs;dTs;dGs;dGs; 
               
               
                 31 
                   
                   
                   
                 G 
                 dTs;dTs;dCs;dTs;dTs;InaTs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 150 
                 GTTTTCCAAACCAG 
                 InaGs;InaTs;InaTs;dTs;dTs;dCs;dCs;d 
               
               
                 32 
                   
                   
                   
                 A 
                 As;dAs;dAs;dCs;dCs;InaAs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 151 
                 ACCAGAGTGTCTGT 
                 InaAs;InaCs;InaCs;dAs;dGs;dAs;dGs; 
               
               
                 33 
                   
                   
                   
                 T 
                 dTs;dGs;dTs;dCs;dTs;InaGs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 152 
                 AGTGTCTGTTGTCC 
                 InaAs;InaGs;InaTs;dGs;dTs;dCs;dTs; 
               
               
                 34 
                   
                   
                   
                 T 
                 dGs;dTs;dTs;dGs;dTs;InaCs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 153 
                 GTTGTCCTTTCTCTC 
                 InaGs;InaTs;InaTs;dGs;dTs;dCs;dCs; 
               
               
                 35 
                   
                   
                   
                   
                 dTs;dTs;dTs;dCs;dTs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 154 
                 CTTTCTCTCTGCCG 
                 InaCs;InaTs;InaTs;dTs;dCs;dTs;dCs;d 
               
               
                 36 
                   
                   
                   
                 A 
                 Ts;dCs;dTs;dGs;dCs;InaCs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 HAMP- 
                 human 
                 HAMP 
                 155 
                 CTGCCGAGTGTCTG 
                 InaCs;InaTs;InaGs;dCs;dCs;dGs;dAs; 
               
               
                 37 
                   
                   
                   
                 T 
                 dGs;dTs;dGs;dTs;dCs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 156 
                 CTCTCCCAAGGTT 
                 InaCs;omeUs;InaCs;omeUs;InaCs;o 
               
               
                 4-27 
                   
                 H4 
                   
                 C 
                 CmeCs;InaCs;omeAs;InaAs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeUs;InaTs;omeCs;InaC-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 157 
                 AGGTTCCTTTCTAT 
                 InaAs;omeGs;InaGs;omeUs;InaTs;o 
               
               
                 4-28 
                   
                 H4 
                   
                 G 
                 meCs;InaCs;omeUs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaAs;omeUs;InaG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 158 
                 ATGTTTATATCATTT 
                 InaAs;omeUs;InaGs;omeUs;InaTs;o 
               
               
                 4-29 
                   
                 H4 
                   
                   
                 meUs;InaAs;omeUs;InaAs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeAs;InaTs;omeUs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 159 
                 ATATCATTTAGCAG 
                 InaAs;omeUs;InaAs;omeUs;InaCs;o 
               
               
                 4-30 
                   
                 H4 
                   
                 G 
                 meAs;InaTs;omeUs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeCs;InaAs;omeGs;InaG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 160 
                 ATTGTTAATGACT 
                 InaAs;omeUs;InaTs;omeGs;InaTs;o 
               
               
                 4-31 
                   
                 H4 
                   
                 A 
                 AmeUs;InaAs;omeAs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeCs;InaTs;omeAs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 161 
                 AGCTTCTAGTTCAG 
                 InaAs;omeGs;InaCs;omeUs;InaTs;o 
               
               
                 4-32 
                   
                 H4 
                   
                 T 
                 meCs;InaTs;omeAs;InaGs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeCs;InaAs;omeGs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 162 
                 AGTGATAGAGCTA 
                 InaAs;omeGs;InaTs;omeGs;InaAs;o 
               
               
                 4-33 
                   
                 H4 
                   
                 TT 
                 meUs;InaAs;omeGs;InaAs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaAs;omeUs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 163 
                 AGAGAGGGAAGAT 
                 InaAs;omeGs;InaAs;omeGs;InaAs;o 
               
               
                 4-34 
                   
                 H4 
                   
                 GA 
                 meGs;InaGs;omeGs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaTs;omeGs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 164 
                 AGTTGATGTGTACA 
                 InaAs;omeGs;InaTs;omeUs;InaGs;o 
               
               
                 4-35 
                   
                 H4 
                   
                 G 
                 meAs;InaTs;omeGs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeAs;InaCs;omeAs;InaG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 165 
                 ACGGGTGCCCAGG 
                 InaAs;omeCs;InaGs;omeGs;InaGs;o 
               
               
                 4-36 
                   
                 H4 
                   
                 AG 
                 meUs;InaGs;omeCs;InaCs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeGs;InaGs;omeAs;InaG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 166 
                 CACAAAACGGCCA 
                 InaCs;omeAs;InaCs;omeAs;InaAs;o 
               
               
                 4-37 
                   
                 H4 
                   
                 GA 
                 meAs;InaAs;omeCs;InaGs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaAs;omeGs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 167 
                 ATATTGCATATATT 
                 InaAs;omeUs;InaAs;omeUs;InaTs;o 
               
               
                 4-38 
                   
                 H4 
                   
                 T 
                 meGs;InaCs;omeAs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeAs;InaTs;omeUs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 168 
                 ATATTTTATTAAAG 
                 InaAs;omeUs;InaAs;omeUs;InaTs;o 
               
               
                 4-39 
                   
                 H4 
                   
                 A 
                 meUs;InaTs;omeAs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeAs;InaAs;omeGs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 169 
                 AGAGTTGTATTCAA 
                 InaAs;omeGs;InaAs;omeGs;InaTs;o 
               
               
                 4-40 
                   
                 H4 
                   
                 T 
                 meUs;InaGs;omeUs;InaAs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeCs;InaAs;omeAs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 170 
                 TGTATTCAATCTTG 
                 InaTs;omeGs;InaTs;omeAs;InaTs;om 
               
               
                 4-41 
                   
                 H4 
                   
                 G 
                 eUs;InaCs;omeAs;InaAs;omeUs;InaC 
               
               
                 m01 
                   
                   
                   
                   
                 s;omeUs;InaTs;omeGs;InaG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 171 
                 CAATCTTGGCAATA 
                 InaCs;omeAs;InaAs;omeUs;InaCs;o 
               
               
                 4-42 
                   
                 H4 
                   
                 A 
                 meUs;InaTs;omeGs;InaGs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeAs;InaTs;omeAs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 172 
                 AGCAAACATAATG 
                 InaAs;omeGs;InaCs;omeAs;InaAs;o 
               
               
                 4-43 
                   
                 H4 
                   
                 GC 
                 meAs;InaCs;omeAs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeUs;InaGs;omeGs;InaC-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 173 
                 ATGGCAACAGGAT 
                 InaAs;omeUs;InaGs;omeGs;InaCs;o 
               
               
                 4-44 
                   
                 H4 
                   
                 TT 
                 meAs;InaAs;omeCs;InaAs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaTs;omeUs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 174 
                 TTTTCTTTGGGAAC 
                 InaTs;omeUs;InaTs;omeUs;InaCs;o 
               
               
                 4-45 
                   
                 H4 
                   
                 A 
                 meUs;InaTs;omeUs;InaGs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaAs;omeCs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 175 
                 ATTCTAATTGGCAA 
                 InaAs;omeUs;InaTs;omeCs;InaTs;o 
               
               
                 4-46 
                   
                 H4 
                   
                 G 
                 meAs;InaAs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeCs;InaAs;omeAs;InaG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 176 
                 ATTGGCAAGCCCTG 
                 InaAs;omeUs;InaTs;omeGs;InaGs;o 
               
               
                 4-47 
                   
                 H4 
                   
                 T 
                 meCs;InaAs;omeAs;InaGs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaTs;omeGs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 177 
                 AGCCCTGTTTGCCT 
                 InaAs;omeGs;InaCs;omeCs;InaCs;o 
               
               
                 4-48 
                   
                 H4 
                   
                 A 
                 meUs;InaGs;omeUs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeCs;InaCs;omeUs;InaA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 178 
                 CTAATTAAATTGAT 
                 InaCs;omeUs;InaAs;omeAs;InaTs;o 
               
               
                 4-49 
                   
                 H4 
                   
                 T 
                 meUs;InaAs;omeAs;InaAs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeGs;InaAs;omeUs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 179 
                 ATTGTTACTTCAAT 
                 InaAs;omeUs;InaTs;omeGs;InaTs;o 
               
               
                 4-50 
                   
                 H4 
                   
                 T 
                 meUs;InaAs;omeCs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeAs;InaAs;omeUs;InaT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 180 
                 TTCTATCTGTTGA 
                 InaTs;omeUs;InaCs;omeUs;InaAs;o 
               
               
                 4-51 
                   
                 H4 
                   
                 C 
                 AmeUs;InaCs;omeUs;InaGs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeGs;InaAs;omeAs;InaC-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 181 
                 CTCTCCCAAGGTTC 
                 InaCs;InaTs;InaCs;dTs;dCs;dCs;dCs;d 
               
               
                 4-27 
                   
                 H4 
                   
                 C 
                 As;dAs;dGs;dGs;dTs;InaTs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 182 
                 AGGTTCCTTTCTAT 
                 InaAs;InaGs;InaGs;dTs;dTs;dCs;dCs; 
               
               
                 4-28 
                   
                 H4 
                   
                 G 
                 dTs;dTs;dTs;dCs;dTs;InaAs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 183 
                 ATGTTTATATCATTT 
                 InaAs;InaTs;InaGs;dTs;dTs;dTs;dAs;d 
               
               
                 4-29 
                   
                 H4 
                   
                   
                 Ts;dAs;dTs;dCs;dAs;InaTs;InaTs;InaT 
               
               
                 m08 
                   
                   
                   
                   
                 -Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 184 
                 ATATCATTTAGCAG 
                 InaAs;InaTs;InaAs;dTs;dCs;dAs;dTs;d 
               
               
                 4-30 
                   
                 H4 
                   
                 G 
                 Ts;dTs;dAs;dGs;dCs;InaAs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 185 
                 ATTGTTAATGACTA 
                 InaAs;InaTs;InaTs;dGs;dTs;dTs;dAs;d 
               
               
                 4-31 
                   
                 H4 
                   
                 A 
                 As;dTs;dGs;dAs;dCs;InaTs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 186 
                 AGCTTCTAGTTCAG 
                 InaAs;InaGs;InaCs;dTs;dTs;dCs;dTs;d 
               
               
                 4-32 
                   
                 H4 
                   
                 T 
                 As;dGs;dTs;dTs;dCs;InaAs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 187 
                 AGTGATAGAGCTA 
                 InaAs;InaGs;InaTs;dGs;dAs;dTs;dAs; 
               
               
                 4-33 
                   
                 H4 
                   
                 TT 
                 dGs;dAs;dGs;dCs;dTs;InaAs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 188 
                 AGAGAGGGAAGAT 
                 InaAs;InaGs;InaAs;dGs;dAs;dGs;dGs; 
               
               
                 4-34 
                   
                 H4 
                   
                 GA 
                 dGs;dAs;dAs;dGs;dAs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 189 
                 AGTTGATGTGTACA 
                 InaAs;InaGs;InaTs;dTs;dGs;dAs;dTs; 
               
               
                 4-35 
                   
                 H4 
                   
                 G 
                 dGs;dTs;dGs;dTs;dAs;InaCs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 190 
                 ACGGGTGCCCAGG 
                 InaAs;InaCs;InaGs;dGs;dGs;dTs;dGs; 
               
               
                 4-36 
                   
                 H4 
                   
                 AG 
                 dCs;dCs;dCs;dAs;dGs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 191 
                 CACAAAACGGCCA 
                 InaCs;InaAs;InaCs;dAs;dAs;dAs;dAs; 
               
               
                 4-37 
                   
                 H4 
                   
                 GA 
                 dCs;dGs;dGs;dCs;dCs;InaAs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 192 
                 ATATTGCATATATT 
                 InaAs;InaTs;InaAs;dTs;dTs;dGs;dCs; 
               
               
                 4-38 
                   
                 H4 
                   
                 T 
                 dAs;dTs;dAs;dTs;dAs;InaTs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 193 
                 ATATTTTATTAAAG 
                 InaAs;InaTs;InaAs;dTs;dTs;dTs;dTs;d 
               
               
                 4-39 
                   
                 H4 
                   
                 A 
                 As;dTs;dTs;dAs;dAs;InaAs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 194 
                 AGAGTTGTATTCAA 
                 InaAs;InaGs;InaAs;dGs;dTs;dTs;dGs; 
               
               
                 4-40 
                   
                 H4 
                   
                 T 
                 dTs;dAs;dTs;dTs;dCs;InaAs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 195 
                 TGTATTCAATCTTG 
                 InaTs;InaGs;InaTs;dAs;dTs;dTs;dCs;d 
               
               
                 4-41 
                   
                 H4 
                   
                 G 
                 As;dAs;dTs;dCs;dTs;InaTs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 196 
                 CAATCTTGGCAATA 
                 InaCs;InaAs;InaAs;dTs;dCs;dTs;dTs;d 
               
               
                 4-42 
                   
                 H4 
                   
                 A 
                 Gs;dGs;dCs;dAs;dAs;InaTs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 197 
                 AGCAAACATAATG 
                 InaAs;InaGs;InaCs;dAs;dAs;dAs;dCs; 
               
               
                 4-43 
                   
                 H4 
                   
                 GC 
                 dAs;dTs;dAs;dAs;dTs;InaGs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 198 
                 ATGGCAACAGGA 
                 InaAs;InaTs;InaGs;dGs;dCs;dAs;dAs; 
               
               
                 4-44 
                   
                 H4 
                   
                 TT 
                 TdCs;dAs;dGs;dGs;dAs;InaTs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 199 
                 TTTTCTTTGGGAAC 
                 InaTs;InaTs;InaTs;dTs;dCs;dTs;dTs;d 
               
               
                 4-45 
                   
                 H4 
                   
                 A 
                 Ts;dGs;dGs;dGs;dAs;InaAs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 200 
                 ATTCTAATTGGCAA 
                 InaAs;InaTs;InaTs;dCs;dTs;dAs;dAs;d 
               
               
                 4-46 
                   
                 H4 
                   
                 G 
                 Ts;dTs;dGs;dGs;dCs;InaAs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 201 
                 ATTGGCAAGCCCTG 
                 InaAs;InaTs;InaTs;dGs;dGs;dCs;dAs; 
               
               
                 4-47 
                   
                 H4 
                   
                 T 
                 dAs;dGs;dCs;dCs;dCs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 202 
                 AGCCCTGTTTGCCT 
                 InaAs;InaGs;InaCs;dCs;dCs;dTs;dGs; 
               
               
                 4-48 
                   
                 H4 
                   
                 A 
                 dTs;dTs;dTs;dGs;dCs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 203 
                 CTAATTAAATTGATA 
                 InaCs;InaTs;InaAs;dAs;dTs;dTs;dAs;d 
               
               
                 4-49 
                   
                 H4 
                   
                 T 
                 s;dAs;dTs;dTs;dGs;InaAs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 204 
                 ATTGTTACTTCAATC 
                 InaAs;InaTs;InaTs;dGs;dTs;dTs;dAs;d 
               
               
                 4-50 
                   
                 H4 
                   
                 T 
                 s;dTs;dTs;dCs;dAs;InaAs;InaTs;InaT 
               
               
                 m08 
                   
                   
                   
                   
                 -Sup 
               
               
                   
               
               
                 NR1H 
                 human 
                 NR1 
                 205 
                 TTCTATCTGTTGAAT 
                 InaTs;InaTs;InaCs;dTs;dAs;dTs;dCs;d 
               
               
                 4-51 
                   
                 H4 
                   
                 C 
                 s;dGs;dTs;dTs;dGs;InaAs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 206 
                 GAATATAGTGGGC 
                 InaGs;omeAs;InaAs;omeUs;InaAs;o 
               
               
                 91 
                   
                   
                   
                 GT 
                 meUs;InaAs;omeGs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeGs;InaCs;omeGs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 207 
                 AGTGGGCGTAGAT 
                 InaAs;omeGs;InaTs;omeGs;InaGs;o 
               
               
                 92 
                   
                   
                   
                 AA 
                 meGs;InaCs;omeGs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaTs;omeAs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 208 
                 CGTAGATAAACTCA 
                 InaCs;omeGs;InaTs;omeAs;InaGs;o 
               
               
                 93 
                   
                   
                   
                 T 
                 meAs;InaTs;omeAs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaCs;omeAs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 209 
                 TAAACTCATAAGCT 
                 InaTs;omeAs;InaAs;omeAs;InaCs;o 
               
               
                 94 
                   
                   
                   
                 T 
                 meUs;InaCs;omeAs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeGs;InaCs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 210 
                 CATAAGCTTAAATT 
                 InaCs;omeAs;InaTs;omeAs;InaAs;o 
               
               
                 95 
                   
                   
                   
                 C 
                 meGs;InaCs;omeUs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeAs;InaTs;omeUs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 211 
                 AAGCTTATAACAGA 
                 InaAs;omeAs;InaGs;omeCs;InaTs;o 
               
               
                 96 
                   
                   
                   
                 T 
                 meUs;InaAs;omeUs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeAs;InaGs;omeAs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 212 
                 ATAACAGATATATT 
                 InaAs;omeUs;InaAs;omeAs;InaCs;o 
               
               
                 97 
                   
                   
                   
                 T 
                 meAs;InaGs;omeAs;InaTs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeAs;InaTs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 213 
                 GATATATTTTCCTG 
                 InaGs;omeAs;InaTs;omeAs;InaTs;o 
               
               
                 98 
                   
                   
                   
                 T 
                 meAs;InaTs;omeUs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaTs;omeGs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 214 
                 TTTCCTGTCTCTTTC 
                 InaTs;omeUs;InaTs;omeCs;InaCs;om 
               
               
                 99 
                   
                   
                   
                   
                 eUs;InaGs;omeUs;InaCs;omeUs;Ina 
               
               
                 m01 
                   
                   
                   
                   
                 Cs;omeUs;InaTs;omeUs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 215 
                 ATGGATTTTTACAT 
                 InaAs;omeUs;InaGs;omeGs;InaAs;o 
               
               
                 100 
                   
                   
                   
                 A 
                 meUs;InaTs;omeUs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeCs;InaAs;omeUs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 216 
                 TGTATGCAGATATA 
                 InaTs;omeGs;InaTs;omeAs;InaTs;om 
               
               
                 101 
                   
                   
                   
                 A 
                 eGs;InaCs;omeAs;InaGs;omeAs;InaT 
               
               
                 m01 
                   
                   
                   
                   
                 s;omeAs;InaTs;omeAs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 217 
                 CTGTAATTATGAAT 
                 InaCs;omeUs;InaGs;omeUs;InaAs;o 
               
               
                 102 
                   
                   
                   
                 A 
                 meAs;InaTs;omeUs;InaAs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaAs;omeUs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 218 
                 TACATAGGCAAAG 
                 InaTs;omeAs;InaCs;omeAs;InaTs;om 
               
               
                 103 
                   
                   
                   
                 AG 
                 eAs;InaGs;omeGs;InaCs;omeAs;InaA 
               
               
                 m01 
                   
                   
                   
                   
                 s;omeAs;InaGs;omeAs;InaG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 219 
                 CAAAGAGTTGCCT 
                 InaCs;omeAs;InaAs;omeAs;InaGs;o 
               
               
                 104 
                   
                   
                   
                 GC 
                 meAs;InaGs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaTs;omeGs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 220 
                 CCAGCCGCTTCCTG 
                 InaCs;omeCs;InaAs;omeGs;InaCs;o 
               
               
                 105 
                   
                   
                   
                 C 
                 meCs;InaGs;omeCs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaTs;omeGs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 221 
                 TAGACATGGATGA 
                 InaTs;omeAs;InaGs;omeAs;InaCs;o 
               
               
                 106 
                   
                   
                   
                 AA 
                 meAs;InaTs;omeGs;InaGs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeGs;InaAs;omeAs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 222 
                 GATGAAATTGCCCC 
                 InaGs;omeAs;InaTs;omeGs;InaAs;o 
               
               
                 107 
                   
                   
                   
                 T 
                 meAs;InaAs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaCs;omeCs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 223 
                 TGCCCCTTGAATGC 
                 InaTs;omeGs;InaCs;omeCs;InaCs;o 
               
               
                 108 
                   
                   
                   
                 G 
                 meCs;InaTs;omeUs;InaGs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeUs;InaGs;omeCs;InaG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 224 
                 TGAATGCGGGTAC 
                 InaTs;omeGs;InaAs;omeAs;InaTs;o 
               
               
                 109 
                   
                   
                   
                 TT 
                 meGs;InaCs;omeGs;InaGs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeAs;InaCs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 225 
                 GTACTTGAAACTAT 
                 InaGs;omeUs;InaAs;omeCs;InaTs;o 
               
               
                 110 
                   
                   
                   
                 T 
                 meUs;InaGs;omeAs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaAs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 226 
                 ACTATTGCATTTCG 
                 InaAs;omeCs;InaTs;omeAs;InaTs;om 
               
               
                 111 
                   
                   
                   
                 T 
                 eUs;InaGs;omeCs;InaAs;omeUs;InaT 
               
               
                 m01 
                   
                   
                   
                   
                 s;omeUs;InaCs;omeGs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 227 
                 CGTTCTCCGGTCCT 
                 InaCs;omeGs;InaTs;omeUs;InaCs;o 
               
               
                 112 
                   
                   
                   
                 G 
                 meUs;InaCs;omeCs;InaGs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeCs;InaCs;omeUs;InaG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 228 
                 CTGTGATGTGAATG 
                 InaCs;omeUs;InaGs;omeUs;InaGs;o 
               
               
                 113 
                   
                   
                   
                 C 
                 meAs;InaTs;omeGs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeAs;InaTs;omeGs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 229 
                 GTTCGAGGATTAG 
                 InaGs;omeUs;InaTs;omeCs;InaGs;o 
               
               
                 114 
                   
                   
                   
                 AC 
                 meAs;InaGs;omeGs;InaAs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeAs;InaGs;omeAs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 230 
                 ATTAGACTGACTGG 
                 InaAs;omeUs;InaTs;omeAs;InaGs;o 
               
               
                 115 
                   
                   
                   
                 A 
                 meAs;InaCs;omeUs;InaGs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaGs;omeGs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 231 
                 ACTGGATTCATTCT 
                 InaAs;omeCs;InaTs;omeGs;InaGs;o 
               
               
                 116 
                   
                   
                   
                 C 
                 meAs;InaTs;omeUs;InaCs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeUs;InaCs;omeUs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 232 
                 ATTCTCATAATTCCT 
                 InaAs;omeUs;InaTs;omeCs;InaTs;o 
               
               
                 117 
                   
                   
                   
                   
                 meCs;InaAs;omeUs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeUs;InaCs;omeCs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 233 
                 ATTCCTACAGCACT 
                 InaAs;omeUs;InaTs;omeCs;InaCs;o 
               
               
                 118 
                   
                   
                   
                 A 
                 meUs;InaAs;omeCs;InaAs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeAs;InaCs;omeUs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 234 
                 TCATTTCATTCCATT 
                 InaTs;omeCs;InaAs;omeUs;InaTs;o 
               
               
                 119 
                   
                   
                   
                   
                 meUs;InaCs;omeAs;InaTs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeCs;InaAs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 235 
                 TCCATTGCCTAGCT 
                 InaTs;omeCs;InaCs;omeAs;InaTs;om 
               
               
                 120 
                   
                   
                   
                 C 
                 eUs;InaGs;omeCs;InaCs;omeUs;Ina 
               
               
                 m01 
                   
                   
                   
                   
                 As;omeGs;InaCs;omeUs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 236 
                 ACCAGGTCACCGG 
                 InaAs;omeCs;InaCs;omeAs;InaGs;o 
               
               
                 121 
                   
                   
                   
                 TT 
                 meGs;InaTs;omeCs;InaAs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeGs;InaGs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 237 
                 CGCAGTAGCTTCCT 
                 InaCs;omeGs;InaCs;omeAs;InaGs;o 
               
               
                 122 
                   
                   
                   
                 A 
                 meUs;InaAs;omeGs;InaCs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeCs;InaCs;omeUs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 238 
                 CAAGGAGTTGACA 
                 InaCs;omeAs;InaAs;omeGs;InaGs;o 
               
               
                 123 
                   
                   
                   
                 TT 
                 meAs;InaGs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aAs;omeCs;InaAs;omeUs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                   
                 THRB 
                 239 
                 ACATTTTGCAGGAC 
                 InaAs;omeCs;InaAs;omeUs;InaTs;o 
               
               
                 124 
                 human 
                   
                   
                 T 
                 meUs;InaTs;omeGs;InaCs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeGs;InaAs;omeCs;InaT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 240 
                 CAAGGAAGGCGCA 
                 InaCs;omeAs;InaAs;omeGs;InaGs;o 
               
               
                 125 
                   
                   
                   
                 CA 
                 meAs;InaAs;omeGs;InaGs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeCs;InaAs;omeCs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 241 
                 ATTAACTTTGCATG 
                 InaAs;omeUs;InaTs;omeAs;InaAs;o 
               
               
                 126 
                   
                   
                   
                 A 
                 meCs;InaTs;omeUs;InaTs;omeGs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeAs;InaTs;omeGs;InaA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 242 
                 TGAATAATGTGAGT 
                 InaTs;omeGs;InaAs;omeAs;InaTs;o 
               
               
                 127 
                   
                   
                   
                 G 
                 meAs;InaAs;omeUs;InaGs;omeUs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aGs;omeAs;InaGs;omeUs;InaG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 243 
                 GTAATTTGGCTAGA 
                 InaGs;omeUs;InaAs;omeAs;InaTs;o 
               
               
                 128 
                   
                   
                   
                 G 
                 meUs;InaTs;omeGs;InaGs;omeCs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aTs;omeAs;InaGs;omeAs;InaG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 244 
                 ACAGTTCCAACTGT 
                 InaAs;omeCs;InaAs;omeGs;InaTs;o 
               
               
                 129 
                   
                   
                   
                 C 
                 meUs;InaCs;omeCs;InaAs;omeAs;In 
               
               
                 m01 
                   
                   
                   
                   
                 aCs;omeUs;InaGs;omeUs;InaC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 245 
                 ATCACTCTGAACAT 
                 InaAs;InaTs;InaCs;dAs;dCs;dTs;dCs;d 
               
               
                 130 
                   
                   
                   
                 T 
                 Ts;dGs;dAs;dAs;dCs;InaAs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 246 
                 GAGCCTATATTCAT 
                 InaGs;InaAs;InaGs;dCs;dCs;dTs;dAs; 
               
               
                 131 
                   
                   
                   
                 A 
                 dTs;dAs;dTs;dTs;dCs;InaAs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 247 
                 ATGCATTTAGGTCT 
                 InaAs;InaTs;InaGs;dCs;dAs;dTs;dTs; 
               
               
                 132 
                   
                   
                   
                 A 
                 dTs;dAs;dGs;dGs;dTs;InaCs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 248 
                 ATGCTGTGATAGA 
                 InaAs;InaTs;InaGs;dCs;dTs;dGs;dTs; 
               
               
                 133 
                   
                   
                   
                 GT 
                 dGs;dAs;dTs;dAs;dGs;InaAs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 249 
                 CATATTAATGCATT 
                 InaCs;InaAs;InaTs;dAs;dTs;dTs;dAs;d 
               
               
                 134 
                   
                   
                   
                 T 
                 As;dTs;dGs;dCs;dAs;InaTs;InaTs;InaT 
               
               
                 m08 
                   
                   
                   
                   
                 -Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 250 
                 TCATCAGCCTGATT 
                 InaTs;InaCs;InaAs;dTs;dCs;dAs;dGs; 
               
               
                 135 
                   
                   
                   
                 A 
                 dCs;dCs;dTs;dGs;dAs;InaTs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 251 
                 TACGGAGTGGACA 
                 InaTs;InaAs;InaCs;dGs;dGs;dAs;dGs; 
               
               
                 136 
                   
                   
                   
                 GT 
                 dTs;dGs;dGs;dAs;dCs;InaAs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 252 
                 CAATCGCAGCGGC 
                 InaCs;InaAs;InaAs;dTs;dCs;dGs;dCs; 
               
               
                 137 
                   
                   
                   
                 TC 
                 dAs;dGs;dCs;dGs;dGs;InaCs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 253 
                 CAGCTGTTGACATG 
                 InaCs;InaAs;InaGs;dCs;dTs;dGs;dTs; 
               
               
                 138 
                   
                   
                   
                 T 
                 dTs;dGs;dAs;dCs;dAs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 254 
                 ATGGAGTTTGGCAT 
                 InaAs;InaTs;InaGs;dGs;dAs;dGs;dTs; 
               
               
                 139 
                   
                   
                   
                 C 
                 dTs;dTs;dGs;dGs;dCs;InaAs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 255 
                 CATGATGAGGAAG 
                 InaCs;InaAs;InaTs;dGs;dAs;dTs;dGs; 
               
               
                 140 
                   
                   
                   
                 TT 
                 dAs;dGs;dGs;dAs;dAs;InaGs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 256 
                 CTCTGTTCCTCAAA 
                 InaCs;InaTs;InaCs;dTs;dGs;dTs;dTs;d 
               
               
                 141 
                   
                   
                   
                 C 
                 Cs;dCs;dTs;dCs;dAs;InaAs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 257 
                 GAATATAGTGGGC 
                 InaGs;InaAs;InaAs;dTs;dAs;dTs;dAs; 
               
               
                 91 
                   
                   
                   
                 GT 
                 dGs;dTs;dGs;dGs;dGs;InaCs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 258 
                 AGTGGGCGTAGAT 
                 InaAs;InaGs;InaTs;dGs;dGs;dGs;dCs; 
               
               
                 92 
                   
                   
                   
                 AA 
                 dGs;dTs;dAs;dGs;dAs;InaTs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 259 
                 CGTAGATAAACTCA 
                 InaCs;InaGs;InaTs;dAs;dGs;dAs;dTs; 
               
               
                 93 
                   
                   
                   
                 T 
                 dAs;dAs;dAs;dCs;dTs;InaCs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 260 
                 TAAACTCATAAGCT 
                 InaTs;InaAs;InaAs;dAs;dCs;dTs;dCs; 
               
               
                 94 
                   
                   
                   
                 T 
                 dAs;dTs;dAs;dAs;dGs;InaCs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 261 
                 CATAAGCTTAAATT 
                 InaCs;InaAs;InaTs;dAs;dAs;dGs;dCs; 
               
               
                 95 
                   
                   
                   
                 C 
                 dTs;dTs;dAs;dAs;dAs;InaTs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 262 
                 AAGCTTATAACAGA 
                 InaAs;InaAs;InaGs;dCs;dTs;dTs;dAs; 
               
               
                 96 
                   
                   
                   
                 T 
                 dTs;dAs;dAs;dCs;dAs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 263 
                 ATAACAGATATATT 
                 InaAs;InaTs;InaAs;dAs;dCs;dAs;dGs; 
               
               
                 97 
                   
                   
                   
                 T 
                 dAs;dTs;dAs;dTs;dAs;InaTs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 264 
                 GATATATTTTCCTG 
                 InaGs;InaAs;InaTs;dAs;dTs;dAs;dTs; 
               
               
                 98 
                   
                   
                   
                 T 
                 dTs;dTs;dTs;dCs;dCs;InaTs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 265 
                 TTTCCTGTCTCTTTC 
                 InaTs;InaTs;InaTs;dCs;dCs;dTs;dGs;d 
               
               
                 99 
                   
                   
                   
                   
                 Ts;dCs;dTs;dCs;dTs;InaTs;InaTs;InaC 
               
               
                 m08 
                   
                   
                   
                   
                 -Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 266 
                 ATGGATTTTTACAT 
                 InaAs;InaTs;InaGs;dGs;dAs;dTs;dTs; 
               
               
                 100 
                   
                   
                   
                 A 
                 dTs;dTs;dTs;dAs;dCs;InaAs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 267 
                 TGTATGCAGATATA 
                 InaTs;InaGs;InaTs;dAs;dTs;dGs;dCs; 
               
               
                 101 
                   
                   
                   
                 A 
                 dAs;dGs;dAs;dTs;dAs;InaTs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 268 
                 CTGTAATTATGAAT 
                 InaCs;InaTs;InaGs;dTs;dAs;dAs;dTs; 
               
               
                 102 
                   
                   
                   
                 A 
                 dTs;dAs;dTs;dGs;dAs;InaAs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 269 
                 TACATAGGCAAAG 
                 InaTs;InaAs;InaCs;dAs;dTs;dAs;dGs; 
               
               
                 103 
                   
                   
                   
                 AG 
                 dGs;dCs;dAs;dAs;dAs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 270 
                 CAAAGAGTTGCCT 
                 InaCs;InaAs;InaAs;dAs;dGs;dAs;dGs; 
               
               
                 104 
                   
                   
                   
                 GC 
                 dTs;dTs;dGs;dCs;dCs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 271 
                 CCAGCCGCTTCCTG 
                 InaCs;InaCs;InaAs;dGs;dCs;dCs;dGs; 
               
               
                 105 
                   
                   
                   
                 C 
                 dCs;dTs;dTs;dCs;dCs;InaTs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 272 
                 TAGACATGGATGA 
                 InaTs;InaAs;InaGs;dAs;dCs;dAs;dTs; 
               
               
                 106 
                   
                   
                   
                 AA 
                 dGs;dGs;dAs;dTs;dGs;InaAs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 273 
                 GATGAAATTGCCCC 
                 InaGs;InaAs;InaTs;dGs;dAs;dAs;dAs; 
               
               
                 107 
                   
                   
                   
                 T 
                 dTs;dTs;dGs;dCs;dCs;InaCs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 274 
                 TGCCCCTTGAATGC 
                 InaTs;InaGs;InaCs;dCs;dCs;dCs;dTs;d 
               
               
                 108 
                   
                   
                   
                 G 
                 Ts;dGs;dAs;dAs;dTs;InaGs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 275 
                 TGAATGCGGGTAC 
                 InaTs;InaGs;InaAs;dAs;dTs;dGs;dCs; 
               
               
                 109 
                   
                   
                   
                 TT 
                 dGs;dGs;dGs;dTs;dAs;InaCs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 276 
                 GTACTTGAAACTAT 
                 InaGs;InaTs;InaAs;dCs;dTs;dTs;dGs; 
               
               
                 110 
                   
                   
                   
                 T 
                 dAs;dAs;dAs;dCs;dTs;InaAs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 277 
                 ACTATTGCATTTCG 
                 InaAs;InaCs;InaTs;dAs;dTs;dTs;dGs; 
               
               
                 111 
                   
                   
                   
                 T 
                 dCs;dAs;dTs;dTs;dTs;InaCs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 278 
                 CGTTCTCCGGTCCT 
                 InaCs;InaGs;InaTs;dTs;dCs;dTs;dCs;d 
               
               
                 112 
                   
                   
                   
                 G 
                 Cs;dGs;dGs;dTs;dCs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 279 
                 CTGTGATGTGAATG 
                 InaCs;InaTs;InaGs;dTs;dGs;dAs;dTs; 
               
               
                 113 
                   
                   
                   
                 C 
                 dGs;dTs;dGs;dAs;dAs;InaTs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 280 
                 GTTCGAGGATTAG 
                 InaGs;InaTs;InaTs;dCs;dGs;dAs;dGs; 
               
               
                 114 
                   
                   
                   
                 AC 
                 dGs;dAs;dTs;dTs;dAs;InaGs;InaAs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                   
                 ATTAGACTGACTGG 
                 InaAs;InaTs;InaTs;dAs;dGs;dAs;dCs; 
               
               
                 115 
                   
                   
                 281 
                 A 
                 dTs;dGs;dAs;dCs;dTs;InaGs;InaGs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                   
                 ACTGGATTCATTCT 
                 InaAs;InaCs;InaTs;dGs;dGs;dAs;dTs; 
               
               
                 116 
                   
                   
                 282 
                 C 
                 dTs;dCs;dAs;dTs;dTs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 283 
                 ATTCTCATAATTCCT 
                 InaAs;InaTs;InaTs;dCs;dTs;dCs;dAs;d 
               
               
                 117 
                   
                   
                   
                   
                 Ts;dAs;dAs;dTs;dTs;InaCs;InaCs;InaT 
               
               
                 m08 
                   
                   
                   
                   
                 -Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 284 
                 ATTCCTACAGCACT 
                 InaAs;InaTs;InaTs;dCs;dCs;dTs;dAs;d 
               
               
                 118 
                   
                   
                   
                 A 
                 Cs;dAs;dGs;dCs;dAs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 285 
                 TCATTTCATTCCATT 
                 InaTs;InaCs;InaAs;dTs;dTs;dTs;dCs;d 
               
               
                 119 
                   
                   
                   
                   
                 As;dTs;dTs;dCs;dCs;InaAs;InaTs;InaT 
               
               
                 m08 
                   
                   
                   
                   
                 -Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 286 
                 TCCATTGCCTAGCT 
                 InaTs;InaCs;InaCs;dAs;dTs;dTs;dGs;d 
               
               
                 120 
                   
                   
                   
                 C 
                 Cs;dCs;dTs;dAs;dGs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 C-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 287 
                 ACCAGGTCACCGG 
                 InaAs;InaCs;InaCs;dAs;dGs;dGs;dTs; 
               
               
                 121 
                   
                   
                   
                 TT 
                 dCs;dAs;dCs;dCs;dGs;InaGs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 288 
                 CGCAGTAGCTTCCT 
                 InaCs;InaGs;InaCs;dAs;dGs;dTs;dAs; 
               
               
                 122 
                   
                   
                   
                 A 
                 dGs;dCs;dTs;dTs;dCs;InaCs;InaTs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 289 
                 CAAGGAGTTGACA 
                 InaCs;InaAs;InaAs;dGs;dGs;dAs;dGs; 
               
               
                 123 
                   
                   
                   
                 TT 
                 dTs;dTs;dGs;dAs;dCs;InaAs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aT-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 290 
                 ACATTTTGCAGGAC 
                 InaAs;InaCs;InaAs;dTs;dTs;dTs;dTs;d 
               
               
                 124 
                   
                   
                   
                 T 
                 Gs;dCs;dAs;dGs;dGs;InaAs;InaCs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 T-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 291 
                 CAAGGAAGGCGCA 
                 InaCs;InaAs;InaAs;dGs;dGs;dAs;dAs; 
               
               
                 125 
                   
                   
                   
                 CA 
                 dGs;dGs;dCs;dGs;dCs;InaAs;InaCs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aA-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 292 
                 ATTAACTTTGCATG 
                 InaAs;InaTs;InaTs;dAs;dAs;dCs;dTs;d 
               
               
                 126 
                   
                   
                   
                 A 
                 Ts;dTs;dGs;dCs;dAs;InaTs;InaGs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 A-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 293 
                 TGAATAATGTGAGT 
                 InaTs;InaGs;InaAs;dAs;dTs;dAs;dAs; 
               
               
                 127 
                   
                   
                   
                 G 
                 dTs;dGs;dTs;dGs;dAs;InaGs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aG-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 294 
                 GTAATTTGGCTAGA 
                 InaGs;InaTs;InaAs;dAs;dTs;dTs;dTs;d 
               
               
                 128 
                   
                   
                   
                 G 
                 Gs;dGs;dCs;dTs;dAs;InaGs;InaAs;Ina 
               
               
                 m08 
                   
                   
                   
                   
                 G-Sup 
               
               
                   
               
               
                 THRB- 
                 human 
                 THRB 
                 295 
                 ACAGTTCCAACTGT 
                 InaAs;InaCs;InaAs;dGs;dTs;dTs;dCs; 
               
               
                 129 
                   
                   
                   
                 C 
                 dCs;dAs;dAs;dCs;dTs;InaGs;InaTs;In 
               
               
                 m08 
                   
                   
                   
                   
                 aC-Sup 
               
               
                   
               
            
           
         
       
     
                     TABLE 4                  A listing of oligonucleotide modifications.                             Symbol   Feature Description                   bio   5′ biotin           dAs   DNA w/3′ thiophosphate           dCs   DNA w/3′ thiophosphate           dGs   DNA w/3′ thiophosphate           dTs   DNA w/3′ thiophosphate           dG   DNA           enaAs   ENA w/3′ thiophosphate           enaCs   ENA w/3′ thiophosphate           enaGs   ENA w/3′ thiophosphate           enaTs   ENA w/3′ thiophosphate           fluAs   2′-fluoro w/3′ thiophosphate           fluCs   2′-fluoro w/3′ thiophosphate           fluGs   2′-fluoro w/3′ thiophosphate           fluUs   2′-fluoro w/3′ thiophosphate           lnaAs   LNA w/3′ thiophosphate           lnaCs   LNA w/3′ thiophosphate           lnaGs   LNA w/3′ thiophosphate           lnaTs   LNA w/3′ thiophosphate           omeAs   2′-OMe w/3′ thiophosphate           omeCs   2′-OMe w/3′ thiophosphate           omeGs   2′-OMe w/3′ thiophosphate           omeTs   2′-OMe w/3′ thiophosphate           lnaAs-Sup   LNA w/3′ thiophosphate at 3′ terminus           lnaCs-Sup   LNA w/3′ thiophosphate at 3′ terminus           lnaGs-Sup   LNA w/3′ thiophosphate at 3′ terminus           lnaTs-Sup   LNA w/3′ thiophosphate at 3′ terminus           lnaA-Sup   LNA w/3′ OH at 3′ terminus           lnaC-Sup   LNA w/3′ OH at 3′ terminus           lnaG-Sup   LNA w/3′ OH at 3′ terminus           lnaT-Sup   LNA w/3′ OH at 3′ terminus           omeA-Sup   2′-OMe w/3′ OH at 3′ terminus           omeC-Sup   2′-OMe w/3′ OH at 3′ terminus           omeG-Sup   2′-OMe w/3′ OH at 3′ terminus           omeU-Sup   2′-OMe w/3′ OH at 3′ terminus           dAs-Sup   DNA w/3′ thiophosphate at 3′ terminus           dCs-Sup   DNA w/3′ thiophosphate at 3′ terminus           dGs-Sup   DNA w/3′ thiophosphate at 3′ terminus           dTs-Sup   DNA w/3′ thiophosphate at 3′ terminus           dA-Sup   DNA w/3′ OH at 3′ terminus           dC-Sup   DNA w/3′ OH at 3′ terminus           dG-Sup   DNA w/3′ OH at 3′ terminus           dT-Sup   DNA w/3′ OH at 3′ terminus           Symbol   Feature Description           bio   5′ biotin           dAs   DNA w/3′ thiophosphate           dCs   DNA w/3′ thiophosphate           dGs   DNA w/3′ thiophosphate           dTs   DNA w/3′ thiophosphate           dG   DNA           enaAs   ENA w/3′ thiophosphate                    
The suffix “Sup” in Table 4 indicates that a 3′ end nucleotide may, for synthesis purposes, be conjugated to a solid support. It should be appreciated that in general when conjugated to a solid support for synthesis, the synthesized oligonucleotide is released such that the solid support is not part of the final oligonucleotide product.
 
     Mouse APOA1 5′ and 3′ termini lancRNA targeting oligos were screened in primary mouse hepatocytes gymnotically at 20 uM, 8 uM and 3.2 uM concentrations in duplicates. APOA1 mRNA was measured and normalized relative to the water control well and B2M housekeeper. As shown in  FIGS. 3A-3C , some of the oligos tested (such as oligos Apoa1_mus-27, 34, 35, 36, 37, 38, and 44) resulted in upregulation of APOA1 mRNA levels. 
     Next, mouse APOA1 5′ and 3′ termini lancRNA targeting oligos were screened in primary mouse hepatocytes gymnotically. APOA1 protein levels were measured in culture media at day5 at 8 uM oligo treatment condition. Abcam ab20453 was used as APOA1 antibody. Treatment with several oligos including Apoa1_mus-27, 35-39, and 41-45 resulted in increased APOA1 protein secretion ( FIGS. 4A-4C ). These results show that oligos targeting regions that encode APOA1 lancRNAs were useful for upregulation of APOA1 levels. 
     Oligos targeting FXN 3′ termini regions in antisense orientation were screened in Sarsero mouse-model derived skin fibroblasts via gymnosis and human FXN mRNA levels were measured. Oligos were screened at 10 uM concentration. Oligo and media changes were performed at day1, day4, day8. Data collection was done at day11. As shown in  FIG. 5 , some of the oligos tested (such as oligos FXN-607, 608, 609, 629, and 634) resulted in upregulation of FXN mRNA levels. 
     Oligos targeting FXN 3′ termini regions in antisense orientation were also screened in GM03816 cells via transfection and human FXN mRNA levels were measured. Oligos were screened at 20 nM and 50 nM concentration. Data collection was done at day4. As shown in  FIG. 6 , some of the oligos tested (such as oligo FXN-650) resulted in upregulation of FXN mRNA levels. 
     Oligos targeting FXN 5′ promoter associated regions in antisense orientation were also screened in GM03816 cells via transfection and human FXN mRNA levels were measured. Except for the oligos FXN-816 to 822, which were screened at three doses, the other oligos were screened at 5 doses. Measurements were taken at day3. As shown in  FIG. 7 , some of the oligos tested (such as oligos FXN-803, 823, 824, 819, and 822) resulted in upregulation of FXN mRNA levels. 
     Oligos targeting FXN 3′ termini regions in antisense orientation were also screened in Sarsero mouse-model derived skin fibroblasts via gymnosis for human FXN protein levels. Measurements were taken at day10. As shown in  FIG. 8 , all of the oligos tested (such as oligos FXN-603, 607, 609, 634, 643) resulted in upregulation of FXN mRNA levels. 
     Oligos targeting FXN 3′ termini regions in antisense orientation were also screened in GM03816 cells via transfection for human FXN mRNA levels. Oligos were screened at 30 nM concentration. Data collection was done at day4. As shown in  FIG. 9 , all of the oligos tested (such as oligos FXN-600, 603, 607, 609, 634, 643) resulted in upregulation of FXN mRNA levels. 
     Next, screens were performed in human normal terminally differentiated cardiomyocytes. 10 uM of oligos were gymnotically delivered to human normal cardiomyocytes. Oligo treatment and media changes were done at day1, day4 and day7. Measurements for RNA and protein were taken at day10. The FXN mRNA data was normalized to GAPDH. FXN-607 showed slight FXN RNA and protein upregulation ( FIGS. 10A-C ). FXN-695 is a FXN gapmer and therefore downregulated FXN levels. 
     Lastly, FXN oligos were tested in vivo. Oligos were injected at 100 mg/kg at day1, day2, day3 subcutaneously to 12-16 week old Sarsero mice. Sarsero mice are an animal model of Fredreich&#39;s Ataxia. The tissue collections were done at day5. The human FXN mRNA levels were measured in liver. The data normalization was done based on GAPDH and total RNA levels. Among others, oligos 607, 634 and 643 showed human FXN upregulation in livers of Sarsero mice ( FIGS. 11A-D ). These results show that oligos targeting regions that encode FXN lancRNAs were useful for upregulation of FXN levels. 
     Together, these data show that oligos targeting regions encoding lancRNAs can be used to upregulate gene expression. 
     The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention.