Patent Publication Number: US-2021171949-A1

Title: Targeting Mirnas for Exosomal Delivery or Cellular Retention

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of International Application No. PCT/US2019/043469 filed Jul. 25, 2019, which claims the benefit of U.S. Provisional Application No. 62/703,566 filed Jul. 26, 2018, the contents of which are incorporated herein by reference in their entirety. 
    
    
     STATEMENT OF FEDERAL FUNDING 
     This invention was made with government support under DK082659 awarded by the National Institute of Health. The government has certain rights in the invention. 
    
    
     BACKGROUND 
     Extracellular vesicles mediate cell to cell communication and are known to play a role in physiological and pathological processes. Extracellular vesicles may derive from the plasma membrane (e.g., microvesicles) or from the endosomal compartment (e.g., exosomes) and deliver their contents from origin to local or distant sites. microRNAs (miRNAs) are a class of non-coding RNAs that function as negative regulators of translation and are involved in many cellular processes. Exosomes carry mRNA, miRNA and other non-coding RNA that can be transferred to recipient cells. miRNAs were discovered in 1993 and are now known to mediate human disease. See Lee et al. (1993) Cell 75, 843-854. For example, it has been described that two human miRNA genes, mir-15a and mir-16-1, are downregulated or deleted in chronic lymphocytic leukemia (CLL). See Calin et al., Proc. Natl. Acad. Sci. USA (2002) 99, 15524-15529. In addition, miRNAs are being explored clinically for the treatment of hepatitis C virus (HCV) infection. See Lindow, M., and Kauppinen, S. (2012). J. Cell Biol. 199, 407-412. 
     Exosomes are extracellular lipid vesicles released by every cell. They contain several classes of macromolecules including DNA, mRNA, proteins and micro-RNAs (miRNAs). Among all these molecules, exosomes seem to be particularly enriched in miRNAs. Exosomes have been demonstrated to be a very efficient delivery tool to transfer macromolecules to target cells where they can exert biological functions. For instance, exosomes can deliver miRNAs to repress gene expression in the target cell. 
     Adipose tissue derived exosomes may have an especially potent effect in delivering miRNAs. Adipose tissue-derived miRNAs are released in vivo into the bloodstream and delivered to the liver, among many other potential tissue targets, where they can regulate hepatic expression of major metabolic genes such as fibroblast growth factor (FGF)-21 (see Thomou et al.,  Nature,  542:450-4555 (2017)). 
     Despite extensive work in the last years, it remains unclear how miRNAs are selected and sorted into exosomes. Santangelo and colleagues described a GGCU motif that can enrich exosomal sorting in the mouse hepatocyte 3A line (see Santangelo et al.  Cell Reports  17:799-808 (2016)), and Villarroya-Beltri and colleagues described a GGAG motif that can enrich exosomal sorting in in human lymphoblasts (see Villarroya-Beltri et al.  Nature Communications  2980 (2013)). However, it is not yet clear whether exosomal sorting motifs can be broad to control sorting in a wide range of cells or alternatively if specific exosomal sorting can be cell-selective and limit sorting in only specific types of cells. 
     The present application describes exosomal sorting and retention motifs that can be used therapeutically to direct miRNAs to desired cellular locations. Described herein are mechanisms that govern the selection of miRNAs into exosomes in a panel of different cell lines. Exosomal sorting motifs showed different levels of enrichment in individual cell lines, meaning that a sorting motif can be optimized to engineer artificial miRNAs by adding or removing a sequence specific to a particular cell type of interest. Similarly, motifs can be engineered to avoid exosomal sorting in particular cell types. 
     SUMMARY 
     In accordance with the description, this study analyzed miRNA motifs responsible for exosomal sorting or cellular retention in different cell lines. Five different mouse cell lines resembling major metabolic cells were cultured in vitro: 3T3-L1 (white adipocytes), BAT (brown adipocytes), C2C12 (muscle cells), AML12 (hepatocytes), and SVEC (vascular endothelial cells). Exosomes and cell lysates were collected, and miRNA profiling was performed to analyze miRNA expression. Motifs that regulate sorting of miRNAs into exosomes in cell-specific manner were determined. Conversely, motifs are described that limit exosomal sorting and enrich retention of miRNAs in the cell. 
     In some embodiments, a method for producing miRNA-containing exosomes or exosome-like vesicles in vitro is provided comprising the steps of modifying a miRNA to include at least one exosomal sorting motif and/or removing any cellular retention motifs, and introducing the modified miRNA into a cell that produces exosomes or exosome-like vesicle under conditions that will result in expression of the modified miRNA. The exosomal sorting motif is selected from UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, and CGGGAG. The cellular retention motif is selected from CAGU, ACAG, AUUG, UAGC, and CCCG. In some embodiments, the method further comprises collecting the produced exosomes or exosome-like vesicles that contain the modified miRNA. 
     In some embodiments, the exosomal sorting motif is UGUG. 
     In some embodiments, the exosomal sorting motif is GGAG. 
     In some embodiments, the exosomal sorting motif is CAUG. 
     In some embodiments, the exosomal sorting motif is GGCA/G. 
     In some embodiments, the exosomal sorting motif is A/CGGG. 
     In some embodiments, the exosomal sorting motif is CUGG. 
     In some embodiments, the exosomal sorting motif is CGGGAG. 
     In some embodiments, the miRNA comprises one exosomal sorting motif. In some embodiments, the miRNA comprises more than one exosomal sorting motif. 
     In some embodiments, subjects are intravenously injected or otherwise administered culture-derived exosomes containing a miRNA of interest and these exosomes deliver their miRNA cargo to a target cell, leading to the reduction of the expression of the gene of interest. In order to induce or increase the export of the desired miRNA to the exosomes, an exosomal sorting motif can be inserted in, or appended to, the miRNA sequence in the cultured cells and/or a cell retention motif removed. In fact, as different cell types seem to have different usage of the motifs (as shown in  FIG. 4 ), the exosomal enrichment may be further optimized by inserting the specific motif that this particular cell type preferentially uses to export its miRNAs. If the miRNA of interest contains a cellular retention motif, this sequence can be removed and replaced by an exosome-enrichment motif, without which exosomal enrichment and potential clinical use might be very limited. 
     Therefore, in some embodiments, the method described above further comprises administering the exosome or exosome-like vesicle to a subject. 
     Therapeutically, exosomes loaded with particular miRNAs may be used to treat diseases where decreasing the expression of a target gene is desired, such as oncogenes in cancer, or inflammatory, lipogenesis- or gluconeogenis-promoting genes in obesity and type 2 diabetes. Thus, in some embodiments, a method of treating a subject in need of gene silencing is provided comprising administering to the subject an exosome, wherein the exosome is produced in vitro by a) modifying a miRNA to include at least one exosomal sorting motif and/or removing any cellular retention motifs, and b) introducing the modified miRNA into a cell that produces exosomes or exosome-like vesicles under conditions that will result in expression of the modified miRNA, and collecting the produced exosome comprising the modified miRNA, wherein the exosomal sorting motif is selected from UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, and CGGGAG and the cellular retention motif, if present, is selected from CAGU, ACAG, AUUG, UAGC, and CCCG. 
     In some embodiments, modifying the miRNA with an exosomal sorting motif results in more miRNA in the exosome as compared to an exosome produced with a miRNA not modified with an exosomal sorting motif. In some embodiments, the removal of the cellular retention motif results in more miRNA in the exosome as compared to an exosome produced with a miRNA comprising a cellular retention motif. 
     In some embodiments, the miRNA contains a cellular retention motif and the cellular retention motif is removed. 
     Conversely, other applications might require miRNA production and retention into the cell. For instance, ex vivo cellular therapies imply the induction of the expression of genes in cells isolated from patients and later reintroduction of those back into the patient. If that gene is a miRNA, a cellular retention motif may be incorporated into its sequence in order to optimize the number of miRNAs that will be retained in the cells and reduce as much as possible its loss through exosomal secretion. In addition, this strategy may reduce the effect in other cells different from the transplanted by limiting the export and transfer of the inserted miRNA to other cells in the organism through exosomes when they are introduced back to the patient. 
     Thus, in some embodiments, a method for retaining miRNA inside a cell in vitro is provided comprising modifying a miRNA to include at least one cell retention motif and/or removing any exosomal sorting motifs, and introducing the modified miRNA into a cell that produces an exosome or exosome-like vesicle under conditions that will result in expression of the modified miRNA, wherein the cell retention motif is CAGU, ACAG, AUUG, UAGC, or CCCG, and the exosomal sorting motif, if present, is UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, or CGGGAG. 
     In some embodiments, a method of treating a subject in need of gene silencing is provided comprising collecting the subject&#39;s cells and manipulating them ex vivo to express an miRNA having at least one cellular retention motif and/or removing any exosomal sorting motifs, and b) administering the ex vivo manipulated cell comprising the modified miRNA to the same or different subject from which it was collected, wherein the cellular retention motif is selected from CAGU, ACAG, AUUG, UAGC, and CCCG, and the exosomal sorting motif, if present, is selected from UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, and CGGGAG. 
     In some embodiments, the cellular retention motif is CAGU. 
     In some embodiments, the cellular retention motif is ACAG. 
     In some embodiments, the cellular retention motif is AUUG. 
     In some embodiments, the cellular retention motif is UAGC. 
     In some embodiments, the cellular retention motif is CCCG. 
     In some embodiments, the miRNA comprises one cellular retention motif. In some embodiments, the miRNA comprises more than one cellular retention motif. 
     In some embodiments, the addition of the cellular retention motif reduces the export of the miRNA into an exosome or exosomal-like vesicle. In some embodiments, the removal of the exosomal sorting motif reduces the export of the miRNA into an exosome or exosomal-like vesicle. 
     In some embodiments, the method further comprises administering the cell to a subject. 
     In some embodiments, the miRNA levels in non-implanted cell-types after administration to the subject are reduced as compared to levels in subject administered a non-modified miRNA containing cell. 
     In some embodiments, the cell is an adipocyte, muscle cell, hepatocyte, or vascular endothelial cell. In some embodiments, the adipocyte is a white adipocyte or brown adipocyte. In some embodiments, the white adipocyte is a 3T3-L1 cell. In some embodiments, the brown adipocyte is a BAT cell. In some embodiments, the muscle cell is a C2C12 cell. In some embodiments, the hepatocyte is an AML12 cell. In some embodiments, the vascular endothelial cell is a SVEC cell. 
     In some embodiments when the cell is a hepatocyte or endothelial cell, the sorting motifs are A/CGGG; CUGG; GGAG; and CGGGAG. 
     In some embodiments when the cell is a brown adipocyte, white adipocyte, or muscle cell, the exosomal sorting motifs are UGUG; CAUG; CUGG; and CGGGAG. 
     In some embodiments, the miRNA is any one of the miRNAs of SEQ ID Nos: 1-704. 
     Additional objects and advantages will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. 
     It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims. 
     The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one (several) embodiment(s) and together with the description, serve to explain the principles described herein. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIGS. 1A-1D  show comparisons of miRNAs among the different cell lines both in the exosomes and cell pellets. By comparing the expression of each miRNA in each cell line with respect to the other four, several cell-type enriched miRNAs for each cell type were identified (shown as outer circles labeled with cell type) in exosomes ( FIG. 1A ) and in the cell pellets ( FIG. 1C ). Other miRNAs were not particularly enriched in any of the studied cell lines (shown as large inner circles). The top-10 enriched miRNAs for each type in the exosomes ( FIG. 1B ) and cell pellets ( FIG. 1D ) are shown. 
         FIGS. 2A-2E  shows analysis of the exosome- and cell lysate-enriched miRNAs for each cell type. The cell lysate refers to the lysate generated from the cell pellet. Most of the miRNAs are specifically found only in the exosomes or in the cell lysate, suggesting the existence of a selective mechanism for exosomal sorting of miRNAs that varies for every cell type. Each cell type also had a smaller number of miRNAs that were present in both the exosome and in the cell lysate (shown in the overlapping region of the exosome and lysate fractions). In some cases, miRNAs detected in exosomes where not detected in the cell lysate and vice-versa; therefore, the total number of miRNAs for each cell type may not match the values in  FIG. 1 . 
         FIG. 3  shows a Venn diagram representing the number of miRNAs with a significant exosomal enrichment (top [“up”] numbers) or cellular enrichment (bottom [“down”] numbers) in each cell type. Overlapping regions indicate the number of miRNAs showing similar enrichment in more than one cell type. 
         FIGS. 4A and 4B  show the main nucleotide motifs significantly enriched in miRNAs that are preferentially sorted into exosomes ( FIG. 4A ) or retained in cells ( FIG. 4B ). The numbers in the table indicate the percentage of miRNAs containing those motifs in each cell type. The presence of two nucleotides at a position means miRNAs were enriched when they contained a motif with either nucleotide at that position. The “total” value represents the percentage of miRNAs from each cell types that contained at least one of the motifs. Some miRNAs contained more than one motif. In this situation, the miRNA is only counted once for the total value, whereas it is counted in both columns referring to those two individual motifs. 
         FIGS. 5A-5E  shows the main nucleotide motifs significantly enriched in miRNAs that preferentially are sorted to exosomes or retained in the cell and the number of miRNAs containing that sequence. The numbers in the left column indicate the order of abundance. 
         FIGS. 6A-6F  show the effects of introducing or removing some sorting motifs.  FIG. 6A  shows the name, mature miRNA sequence, and introduced motif for the new miRNA constructs from miR-34c-5p and its wild-type version. Bold underlined text indicate nucleotides that were replaced. The miRNA constructs tested were miR-34c-5p wt (SEQ ID NO: 648), miR-34c-5p-UGUG (SEQ ID NO: 701), miR-34c-5p-CAUG (SEQ ID NO: 702), and miR-34c-5p-CGGGAG (SEQ ID NO: 703).  FIG. 6B  shows the predicted hairpin structure upon the nucleotide replacements (arrows) in the changes in the nucleotides in the guide strand (described in  FIG. 6A ) and the passenger strand. High pairing possibility between nucleotides is shown in black, while low pairing probability in gray.  FIG. 6C  shows exosomal enrichment measured as the difference between normalized expression of each miRNA version in exosomes divided by the normalized expression in the cell. In both exosomes and cells, expression was normalized in respect to miR-138b-5p, which was shown to be equally abundant in both exosomes and cells. *P-value&lt;0.05. 
         FIG. 6D  shows the name, mature miRNA sequence, and introduced motif for a new miRNA construct miR-693-3p-mut (SEQ ID NO: 704) and wild-type miR-693-3p (SEQ ID NO: 6). Bold underlined text indicates the nucleotide that was replaced.  FIG. 6E  shows the predicted hairpin structure for miR-693-3p wild-type and the mutated version upon the nucleotide replacements (arrow) in the changes in the nucleotides in the guide strand (described in  FIG. 6D ) and the passenger strand. High pairing possibility between nucleotides is shown in black, while low pairing probability in gray.  FIG. 6F  shows exosomal enrichment measured as the difference between normalized expression of each miRNA version in exosomes divided by normalized expression in the cell. In both exosomes and cells, expression was normalized in respect to miR-138b-5p. **P-value&lt;0.01. 
     
    
    
     DESCRIPTION OF THE EMBODIMENTS 
     “Exosomes” as used herein are membrane-surrounded, endosomal-derived vesicles that are present in many biological fluids, including blood, urine, and cultured medium of cell cultures. Exosomes may also be referred to as secreted vesicles. It will be understood that exosomes as described herein may, in certain non-limiting embodiments, also encompass exosome-like vesicles that may vary somewhat from typical exosomes but are still functionally and/or structurally similar or related. Reference to exosome-producing cells herein may include other suitable exosome-like vesicle-producing cells which produce exosome-like vesicles which may vary somewhat from typical exosomes but are still functionally and/or structurally similar or related. For instance, exosomes as described herein may include, in certain non-limiting embodiments, other suitable exosome-like vesicles between 50-150 nm (which contain exosomal markers), and/or larger exosome-like vesicles of 100-600 nm. 
     “microRNA” or “miRNA” as used herein refers to small non-coding RNA molecules that are evolutionary conserved. miRNAs are naturally occurring in an organism. Alternatively, a miRNA may be designed artificially and not be present in any organism. A miRNA may be chemically modified, for example, to improve stability. A miRNA may affect RNA silencing and post-transcriptional regulation of gene expression. 
     “Protein” as used herein, is a protein, polypeptide, or peptide. As such, a “protein” as used in this application may refer to only a portion of a full-length protein that is the product of a gene. 
     “Cell (or cellular) retention motif,” as used herein, refers to a sequence of nucleotides that when naturally or artificially present or appended to a miRNA cause the miRNA to be substantially retained in the endosome. 
     “Exosome (or exosomal) sorting motif,” as used herein, refers to a sequence of nucleotides that when naturally or artificially present or appended to a miRNA cause the miRNA to be substantially present or exported to or into an exosome. 
     miRNA constructs (also sometimes referred to herein as “miRNA”) as described herein may be chemically synthesized using, for example, solid phase synthesis, or other methods known in the art. miRNA may also be prepared by cellular or in vitro expression from a suitable expression vector as will be known in the art. Variants, chemically modified analogues, and structural mimics of miRNA as described herein may also be possible. 
     miRNA constructs may be introduced into a cell, expressed in a cell, or caused to be produced by a cell, using any of a number of well-known methods. Introduction of a miRNA into a cell may include expression of the nucleic acid construct within a cell using a method as described herein, or using a suitable method known in the art, and/or may include direct introduction of the miRNA construct into the cell via, for example, transfection. Expression vectors (either viral, plasmid, or other) may be transfected, electroporated, or otherwise introduced into cells, which may then express the miRNA construct(s). Alternatively, nucleic acid constructs themselves may be directly introduced into cells, for example via transfection or electroporation (i.e. using a transfection reagent such as but not limited to Lipofectamine™, Oligofectamine, or any other suitable delivery agent known in the art), or via targeted gene or nucleic acid delivery vehicles known in the art. Many delivery vehicles and/or agents are well-known in the art, several of which are commercially available. Delivery strategies for nucleic acids are described in, for example, Yuan et al., Expert Opin. Drug Deliv. (2011) 8:521-536; Juliano et al, (2012) Acc. Chem. Res. 45: 1067-1076; and Rettig et al. Mol. Ther. (2012) 20: 483-512. Examples of transfection methods are described in, for example, Ausubel et al. (1994) Current Protocols in Molecular Biology, John Wiley &amp; Sons, New York. Expression vector examples are described in, for example, Cloning Vectors: A Laboratory Manual (Pouwels et al., 1985, Supp. 1987). It will be understood that introduction of a nucleic acid construct into a cell may refer to the production of a nucleic acid within a cell from a gene (i.e. transcription), such an exogenous gene which has been introduced into the cell. 
     In some embodiments, a cell already expresses a miRNA and that miRNA is modified in vitro to contain an exosomal sorting or cellular retention motif. 
     In some embodiments, the miRNA comprises a native sequence that is present in the subject organism. In some embodiments, the miRNA does not comprise a native sequence. In some embodiments, the miRNA is non-natural. 
     In some embodiments, the miRNA is non-naturally prepared ex vivo. In some embodiments, the miRNA alters gene function. 
     Autologous or heterologous exosomes may be prepared. 
     In some embodiments, autologous exosomes are prepared. “Autologous exosomes” refers to exosomes that are prepared from the same subject who would receive the exosomes after ex vivo manipulation. 
     In some embodiments, heterologous exosomes are prepared. “Heterologous exosomes” refer to exosomes that are prepared from a different individual than the subject who receives the exosomes after ex vivo manipulation. 
     In some embodiments, the exosomes are produced by cells in vitro. In some embodiments, the isolated exosomes are formed inside the cell in compartments known as multivesicular endosomes (MVE) or multivesicular body (MVB). In some embodiments, exosomes are released from a cell without a trigger or signal. In some embodiments, exosomes are released from a cell based on a signal, such as binding of a cell-surface receptor. 
     In some embodiments, exosomes are approximately 30 to 100 nm, 20 to 90 nm, 30 to 80 nm, 40 to 70 nm, or 50 to 60 nm. In some embodiments, exosomes are approximately 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, or 200 nm in size. 
     In some embodiments, the exosomes are derived from adipose tissue. In some embodiments, exosomes secreted from fat or adipose tissue may be termed fat-derived exosomes. In some embodiments, this adipose tissue can be inguinal, epididymal, or brown adipose tissue (BAT). In some embodiments, this adipose tissue can be brown fat, beige fat, or white fat. 
     In some embodiments, an exosome is derived from BAT tissue. In some embodiments, BAT is characterized by numerous small lipid droplets and a higher concentration of mitochondria compared with white fat. In some embodiments, BAT occurs in high concentrations in certain anatomical locations, such as between the shoulder blades, surrounding the kidneys, the neck and supraclavicular area, and along the spinal cord. In some embodiments, BAT occurs in the upper chest and neck, especially paravertebrally. 
     This description and exemplary embodiments should not be taken as limiting. For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing quantities, percentages, or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about,” to the extent they are not already so modified. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. 
     It is noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the,” and any singular use of any word, include plural referents unless expressly and unequivocally limited to one referent. As used herein, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items. 
     EXAMPLES 
     The following examples are provided to illustrate certain disclosed embodiments and are not to be construed as limiting the scope of this disclosure in any way. 
     Example 1. Cell Lines 
     This study analyzed 5 different mouse cell lines resembling major metabolic cells: 3T3-L1 (white adipocytes), BAT (brown adipocytes), C2C12 (muscle cells), AML12 (hepatocytes) and SVEC (vascular endothelial cells). 
     3T3-L1 cells (ATCC, catalog nr CL-173) were grown in growth medium (DMEM-high glucose supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin, and 0.2% normocin). For the experiments, cells were grown to reach full confluence and differentiated to mature adipocytes. Upon addition of differentiation cocktail containing 0.5 mM IBMX, insulin 5 μg/mL and dexamethasone 0.25 μM in growth medium for 72 hours, cells were maintained in growth medium only supplemented with insulin 5 μg/ml for 8 days to obtain fully differentiated adipocytes. 
     Brown pre-adipocytes (BAT) were generated as described previously (Fasshauer M et al.,  J Biol Chem  275(33):25494-501 (2000)) and grown in DMEM-high glucose, 20% fetal bovine serum, 1% penicillin/streptomycin and 0.2% normocin. For the experiments, cells were grown to full confluence and differentiated to mature brown adipocytes. To induce differentiation, cells were incubated for 24 hours in growth medium supplemented with 0.5 mM IBMX, 0.125 mM indomethacin, 2 μg/ml dexamethasone, 20 nM insulin, and 1 nM T3 hormone. After that, cells were grown in culture medium only supplemented with 20 nM insulin and 1 nM T3 for 6 days. All reagents for 3T3-L1 and BAT differentiation were purchased from Millipore-Sigma. 
     AML12 hepatocytes were purchased from ATCC (catalog nr CRL-2254) and grown in DMEM/F12 high glucose, 10% fetal bovine serum, 1% penicillin/streptomycin and 0.2% normocin supplemented with insulin-transferrin-selenium-sodium pyruvate mixture (ITS-A, Thermofisher), 2.5 mM L-Glutamine (Thermofisher), 15 mM HEPES (Millipore-Sigma) and dexamethasone 40 ng/ml. 
     SVEC endothelial cells were purchased from ATCC (catalog nr CRL-2181) and cultured in growth medium. 
     C2C12 myoblasts (ATCC, catalog nr CRL-1772) were grown in growth medium. Upon confluence, cells were differentiated by growing the cells in DMEM-high glucose supplemented with 2% horse serum, 1% penicillin/streptomycin and 0.2% normicin for 6 days and used for the experiments. 
     Example 2. Exosome Isolation and Analysis 
     For exosome isolation, all cell lines cells were grown to full confluence. When cells required differentiation (3T3-L1, BAT, and C2C12), they were differentiated as described in Example 1. To collect exosomes, cells were washed with PBS and incubated for 72 hours in exosome-free medium consisting of DMEM-high glucose, 10% exosome-depleted fetal bovine serum (SBI), and 1% penicillin/streptomycin. Medium was collected and exosomes were isolated by differential centrifugation protocol (Thery C et al.,  Curr Protoc Cell Biol Chapter  3: Unit 3.22 (2006)). Briefly, medium was successively centrifuged at 500 g, 2,000 g and 10,000 g. Supernatant was later ultracentrifuged at 100,000 g for 70 min using a SW-28 rotor. Pellets were washed with PBS and centrifuged again at 100,000 g for 70 min. Pellets were resuspended in 1 mL TRIzol reagent (Thermofisher) to generate a cell lysate for further RNA isolation. 
     Similarly, cells that had produced the exosomes were washed with PBS after the incubation in exosome-free medium and 1 mL TRIzol reagent was added for further RNA isolation. This sample represents the cell lysate. 
     For RNA isolation and miRNA profiling, samples in TRIzol were added to 200 μL chloroform (Millipore-Sigma). After mixing, samples were centrifuged at 12,000 g for 15 min. Upper liquid phase was collected and RNA was precipitated by adding 2-propanol (Millipore-Sigma) and ammonium acetate (Millipore-Sigma) and incubating at −20° C. overnight. Samples were centrifuged at 12,000 g for 30 min and RNA pellets were washed twice with 70% ethanol and resuspended in nuclease-free water (Qiagen). Both exosomal and cell pellet miRNA profilings were performed using a mouse a QuantiMir for cDNA synthesis (SBI) and miRNome miRNA profiling kit (SBI) following manufacturer&#39;s protocol. RNA amount used for the experiment was 275 ng per sample. 
     For bioinformatic analysis, an arbitrary threshold (80) was used to extract ct value from the qPCRs. Samples that did not have ct value&lt;=35 in at least 2 of the replicates for a given miRNA were considered non-detected and therefore filtered out. Ct values were normalized using mean ct of all detected miRNAs of each sample. Package Limma for R software (Ritchie M E et al.,  Nucleic Acids Research  43(7), e47 (2015)) was used for the analysis. Bioinformatics was used to compare the normalized expression in the cell and in the exosome of each given miRNAs with a false discovery rate (FDR) of &lt;0.1. When the FDR for a given miRNA was &lt;0.1, it was considered significant. 
     Example 3. Identification of Cell Type-Enriched miRNAs in Exosomal and Cellular Fractions 
     Cells described in Example 1 were cultured in exosome-free medium, and exosomes were collected from the medium after 72 hours. RNA was isolated from the collected exosomes as well as from the cell pellets, converted to cDNA and subjected to a qPCR-based miRNA profiling to detect miRNA expression. 
     Among the 709 mouse miRNAs analyzed included in the miRNA profiling kit, 697 were detected in at least one of the cell types. By comparing the expression of each miRNA in each cell type to the expression in the other four, several miRNAs were identified that were particularly enriched in the exosomes derived from one of the cell types.  FIGS. 1A  (exosomes) and  1 C (cell pellets) shows overall counts of miRNAs that had enrichment in a particular cell type. The outer circles in  FIGS. 1A and 1C  show the number of miRNAs with enrichment in a particular cell type. Similarly, some other miRNAs were found selectively in the cell pellets from one particular cell type. 
     The top-10 enriched miRNAs for each cell type in exosomes ( FIG. 1B ) and cell pellets ( FIG. 1D ). Different cell types had different miRNAs with higher enrichment, and miRNAs that were enriched in one particular cell type were not necessarily highly expressed in other cell types. 
     As expected, most measured miRNAs were not uniquely representative of one of the cell types either in the exosomal (453 miRNAs) or in the cellular fraction (467 miRNAs) ( FIGS. 1A and 1C ). Some of the cell-enriched miRNAs were previously reported to mediate important functions in the tissues that these cells resemble. For instance, miR-19a and miR-122 that were significantly higher in AML12 hepatocytes ( FIGS. 1B and 1D ) are known to be expressed in mouse liver where they regulate glycogen synthesis and lipid metabolism, respectively (see Dou L et al.,  Sci Rep  26(5):11602 (2015) and Esau C et al.,  Cell Metab  3(2):87-98 (2006)). Other examples are miR-1 and miR-133a/b that were found to be enriched in C2C12 myotubes and previously reported to mediate crucial functions in skeletal muscle and heart (see Zhao Y et al., Cell 129(2):303-317 (2007) and Chen J F et al.,  Nat Genet  38(2):228-33 (2006)). Similarly, miR-146b seems to activate adipogenesis and was enriched in 3T3-L1 adipocytes (see Ahn J et al.,  EMBO Mol Med  10:1602-12 (2013)). All these data suggest that this study efficiently identified cell-type enriched miRNAs and that the cell lines used here resemble metabolic distinct tissues. 
     After identifying exosome and cell pellet-specific miRNAs, the miRNA population contained in the exosomes was compared to the cellular content of each cell type. If exosomes simply represent a sample of the miRNAs that are found in the cell, there should be a perfect match between the specific miRNAs found in exosomes and the cell pellets for each cell type. If, in contrast, there is selectivity in the loading of exosomes, populations of exosomal and cellular miRNAs would be at least partially different. 
     As shown in  FIGS. 2A-2E , there is an incomplete match in the miRNA population between exosome and cell lysate samples from each cell type. Some miRNAs are cell type-specific regarding both compartments, as shown by the number of miRNAs contained in the region of overlap between the exosome and lysate samples for each cell type. However, many other miRNAs were selectively found in the cellular or in the exosome fraction of a given cell type, and they were not specifically found in the other fraction. These data suggest the presence of a sorting mechanism of miRNAs into exosomes that is specific for one cell type versus another. 
     Example 4. Enrichment and Depletion of miRNAs from Exosomes 
     In order to understand how some miRNAs are preferentially loaded into the exosomes whereas others preferentially remain in the cell, the expression of each particular miRNA was compared between the exosomal and the cellular fraction. This approach allowed separation of miRNAs that are particularly enriched in the exosomes compared to the cells where they were produced (expression in exosomes would be significantly higher than in the cell), or in contrast miRNAs that are enriched in the cell pellets but rarely go to the exosomes (expression significantly lower in the exosomes than in the cell). As shown in  FIG. 3 , miRNAs were identified with a significant enrichment in the exosomes (top [“up”] values) or in the cell pellet (bottom [“down”] values) in each cell type. The sorting into up and down groups was done by comparing the normalized expression of a miRNA in the exosome (measured by comparing to the mean of all detected miRNAs) to the normalized expression in the cell pellet. For a miRNA to be placed “up”, it needed to have a significant higher expression in the exosome compared to cell lysate as determined by a cut-off&lt;0.1 in the false discovery rate. Similarly for a miRNA to be placed “down,” it needed to have a significant higher expression in the cell pellet compared to cell lysate as determined by a cut-off&lt;0.1 in the false discovery rate. 
     A total of 19 miRNAs were identified that were significantly enriched in the exosomes from every cell type, and 49 miRNAs were identified that were significantly depleted from the exosomes of all cell lines analyzed in this study; these data are shown in the center values that overlapped between all cell types. Another interesting finding is the high degree of similarity between brown adipocytes (BAT) and muscle cells (C2C12) regarding which miRNAs are enriched or depleted in the exosomes ( FIG. 3 ), as represented by the high number of miRNAs (35) enriched in exosomes shared by both cell types. Similarly, the number of miRNAs (27) in the intersection of BAT, C2C12, and 3T3-L1 cells is also high, which further contributes to the finding of similarity in enrichment data between BAT and C2C12 cells. 
     Example 5. Identification of RNA Motifs Associated with Exosomal or Cellular miRNA Enrichment in Different Cell Types 
     The potential mechanism that made some miRNAs preferentially sorted to exosomes or be retained in the cell was explored. In particular, nucleotide sequences of the miRNAs were investigated to determine if they could determine the fate of the sorting. 
     Table 1 shows all detected miRNAs and their mature sequences. The code 1 indicates significant enrichment of that miRNA expression in exosomes from the cell type referred in the column, code −1 indicates significant cell enrichment, and code 0 indicates no difference between exosomal and cellular expression. The identified exosomal enrichment motifs are highlighted in bold whereas the cellular enrichment motifs are underlined. Some miRNAs did not comprise either an exosomal sorting motif or a cellular retention motif. Some miRNAs comprised both an exosomal sorting motif and in a cellular retention motif. Nucleotides that were within both an exosomal sorting and within a cellular retention motif are noted with bold underlined font. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Detected miRNAs and their sorting in different cells 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Sequence [Exosomal 
                   
                   
                   
                   
                   
                   
               
               
                   
                 sorting motifs 
                   
                   
                   
                   
                   
                   
               
               
                   
                 are in bold and 
                   
                   
                   
                   
                   
                   
               
               
                 SEQ 
                 cellular retention 
                   
                   
                   
                   
                   
                   
               
               
                 ID 
                 motifs are in 
                   
                   
                   
                   
                   
                   
               
               
                 No 
                 underline 
                 miRNAs 
                 3T3-L1 
                 C2C12 
                 SVEC 
                 AML12 
                 RAT 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 gggggu ccccg gugcucggauc 
                 mmu-miR-615-5p 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 2 
                   auug cuucccagacggugaaga 
                 mmu-miR-686 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 3 
                 cgugggccugacgu ggagcugg   
                 mmu-miR-770-3p 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 4 
                 aaaucuaccugccucugccu 
                 mmu-miR-1196 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 5 
                 aggaagcc cuggaggg g cuggag   
                 mmu-miR-671-5p 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 6 
                 gcagcuuucaga ugug gcuguaa 
                 mmu-miR-693-3p 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 7 
                 ugucug cccg agugccugccucu 
                 mmu-miR-346 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 8 
                   ggcgcgggcgcugg acgccucg 
                 mmu-miR-1893 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 9 
                 uaa ggca cgcggugaaugcc 
                 mmu-miR-124 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 10 
                 gagcagcagaggau cuggag gu 
                 mmu-miR-1907 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 11 
                 acguuggcu cugg uggugaug 
                 mmu-miR-1306 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 12 
                 auagu ugugugug ga ugug ugu 
                 mmu-miR-669c 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 13 
                 a ggca   gu guugu uag cugg   c 
                 mmu-miR-449b 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 14 
                 gcuucuc cugg cucuccucccuc 
                 mmu-miR-207 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 15 
                 gucucggugcaagga cuggag g 
                 mmu-miR-678 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 16 
                 acca ggag gcugaggucccu 
                 mmu-miR-665 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 17 
                 a agggag gau cugggca c cugg a 
                 mmu-miR-1943 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 18 
                   cugg u acag gc cugg gggauag 
                 mmu-miR-150* 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 19 
                 cagccucg cuggcaggca gcu 
                 mmu-miR-681 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 20 
                 uuu auug agcaccuccuaucaa 
                 mmu-miR-325 
                 1 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 21 
                 aggucagaggucgauc cugg   
                 mmu-miR-540-3p 
                 1 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 22 
                 uuugaaccaucacucgacuccu 
                 mmu-miR-434-3p 
                 1 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 23 
                 acuguacaggccacugccuugc 
                 mmu-let-7g* 
                 1 
                 1 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 24 
                 a ggca   gu gc auug c uag cugg     
                 mmu-miR-449c 
                 1 
                 1 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 25 
                 ugaagguccuac ugug ugccagg 
                 mmu-miR-493 
                 1 
                 1 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 26 
                 aaacaaa caug gugcacuucuu 
                 mmu-miR-495 
                 1 
                 1 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 27 
                 ugauc uagc caaagccugacugu 
                 mmu-miR-344 
                 1 
                 1 
                 1 
                 −1 
                 1 
               
               
                   
               
               
                 28 
                 augua ugug ug caugugcaug u 
                 mmu-miR-297a 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 29 
                   ugug ug caugugcaugug uguaa 
                 mmu-miR-466j 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 30 
                 acg ugugugugcaugugcaug u 
                 mmu-miR-466f 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 31 
                 ugag ugugugugugug ag ugug u 
                 mmu-miR-574-5p 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 32 
                 agu ugugugugcaug uauaugu 
                 mmu-miR-6691 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 33 
                   ugug ug caugug cu ugug ugua 
                 mmu-miR-466h 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 34 
                 auaag ugug ug caug uauaugu 
                 mmu-miR-467h 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 35 
                 ua ugugugug ugua ugug uguaa 
                 mmu-miR-1187 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 36 
                 uacg ugugugugcaugugcaug   
                 mmu-miR-466f-5p 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 37 
                 ggugcuca caug uccuccu 
                 mmu-miR-764-5p 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 38 
                 ccu cugg gcccuuccuc cagu   
                 mmu-miR-326 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 39 
                 ccacugccccaggugcugcu 
                 mmu-miR-324-3p 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 40 
                 uucccuuugucauccuuugccu 
                 mmu-miR-211 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 41 
                 uaagugcuuc caug uuugagugu 
                 mmu-miR-302d 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 42 
                 gcacugagaug ggag uggugua 
                 mmu-miR-674 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 43 
                 ca aggg ucacccucugacucugu 
                 mmu-miR-540-5p 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 44 
                 ugucuugcaggccgu caug ca 
                 mmu-miR-431 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 45 
                 ccugaacu aggg gu cuggag ac 
                 mmu-miR-345-3p 
                 1 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 46 
                 agucauacacggcucuccucuc 
                 mmu-miR-485* 
                 1 
                 1 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 47 
                 auu ugugugug ga ugug ugu 
                 mmu-miR-669n 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 48 
                   ggca ga ggaggg cuguucuuccc 
                 mmu-miR-298 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 49 
                   ugug uca cugg ggauaggcuuug 
                 mmu-miR-1970 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 50 
                 ga ugugugug ug caug uacaua 
                 mmu-miR-466c-5p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 51 
                 cgucaacacuug cugg uuuucu 
                 mmu-miR-505 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 52 
                 ucucccaacccuuguac cagu g 
                 mmu-miR-150 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 53 
                   ugugugug ua caug ua caugug a 
                 mmu-miR-466k 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 54 
                 aagugcuuc caug uuu cagu gg 
                 mmu-miR-302c 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 55 
                 a ggag gccauagu ggca acugu 
                 mmu-miR-764-3p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 56 
                 ugcagcagccuga ggcaggg cu 
                 mmu-miR-1906 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 57 
                 agaggug cagu a ggcaug acuu 
                 mmu-miR-1902 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 58 
                 a cggg uuaggcucuug ggag cu 
                 mmu-miR-125b-3p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 59 
                 uaugacuga ugug cg ugug ucug 
                 mmu-miR-468 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 60 
                 uauaca agggca agcucucugu 
                 mmu-miR-381 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 61 
                 caac cuggag gacuc caug cug 
                 mmu-miR-490 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 62 
                 aaagugccgccuaguuuuaagccc 
                 mmu-miR-290-3p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 63 
                 aaugacaccacauauau ggca gc 
                 mmu-miR-489 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 64 
                 aaucgu ac aggg   ucauccacuu 
                 mmu-miR-487b 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 65 
                 augua ugug ug caug ua caug u 
                 mmu-miR-297c 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 66 
                 ugccucuuuc auug aucuuggu 
                 mmu-miR-469 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
                 gucc 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 67 
                 uaacacugu cugg uaaagaugg 
                 mmu-miR-141 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 68 
                   agggag aug cugg u acag aggcuu 
                 mmu-miR-1941-5p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 69 
                 uauguaguaugguccacaucuu 
                 mmu-miR-380-3p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 70 
                 aaagugcauccauuuuguuugu 
                 mmu-miR-291b-3p 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 71 
                 uacguaguauagugcuuuucac 
                 mmu-miR-471 
                 1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 72 
                 uucagcuccuauaugaugccu 
                 mmu-miR-337-3p 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 73 
                 uuuuucauu auug cuccugacc 
                 mmu-miR-335-3p 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 74 
                 aacauagaggaaauuucacgu 
                 mmu-miR-376c 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 75 
                 ugaccgauuucuc cugg uguuc 
                 mmu-miR-29c* 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 76 
                 gcagc aggg ugaaacugacaca 
                 mmu-miR-761 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 77 
                   cagu   caug ccgcuugccuacg 
                 mmu-miR-707 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 78 
                 uuauaaagcaaugagacugauu 
                 mmu-miR-340-5p 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 79 
                 aucacacaaa ggca acuuuugu 
                 mmu-miR-377 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 80 
                 ugcacuga aggca c acag c 
                 mmu-miR-713 
                 1 
                 1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 81 
                 aauauaac acag auggccugu 
                 mmu-miR-410 
                 1 
                 1 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 82 
                 augua ugug ug caug aa caug u 
                 mmu-miR-297b-5p 
                 1 
                 1 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 83 
                 ucacuccuccccu cccg ucuu 
                 mmu-miR-483* 
                 1 
                 0 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 84 
                 gagcuuauucauaaaagugcag 
                 mmu-miR-590-5p 
                 1 
                 0 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 85 
                 ucgugucu ugug uugcagccgg 
                 mmu-miR-187 
                 1 
                 0 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 86 
                 gagu auug uuuccacugc cugg   
                 mmu-miR-503* 
                 1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 87 
                 aaugcac cugggcaaggg uuca 
                 mmu-miR-500 
                 1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 88 
                 au caug augggcuccucggugu 
                 mmu-miR-433 
                 1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 89 
                 gaac ggcg u caug ca ggag uu 
                 mmu-miR-337-5p 
                 1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 90 
                 uccuguacugagcugc cccg ag 
                 mmu-miR-486 
                 1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 91 
                 ugcgagucacc cc cggg   uguug 
                 mmu-miR-712* 
                 1 
                 0 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 92 
                 ucggucgaucggucggucggu 
                 mmu-miR-341 
                 1 
                 0 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 93 
                 cu cggg gaucau caug ucacga 
                 mmu-miR-542-5p 
                 1 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 94 
                 uu auug cuuaagaauacgcguag 
                 mmu-miR-137 
                 1 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 95 
                 ucuucg cggg uacugu cggg ac 
                 mmu-miR-1945 
                 1 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 96 
                 cauaaaguagaaagcacuacu 
                 mmu-miR-142-5p 
                 1 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 97 
                   caug guucugucaagcaccgcg 
                 mmu-miR-218-2* 
                 1 
                 0 
                 1 
                 0 
                 −1 
               
               
                   
               
               
                 98 
                 ccaagugcucagaugcu ugug gu 
                 mmu-miR-105 
                 1 
                 0 
                 1 
                 −1 
                 0 
               
               
                   
               
               
                 99 
                 au ggag gacugagaaggu ggag   
                 mmu-miR-1940 
                 1 
                 0 
                 1 
                 −1 
                 0 
               
               
                   
                   cagu u 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 100 
                 ua ugug ggacgguaaaccgcuu 
                 mmu-miR-299 
                 1 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 101 
                 aggucaagguuc ac aggg   gauc 
                 mmu-miR-1898 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 102 
                 ugcagcuguuaaggaugguggacu 
                 mmu-miR-1968 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 103 
                 auaagacgagcaaaaagcuugu 
                 mmu-miR-208a 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 104 
                   cagu gguagagcauaugac 
                 mmu-miR-1957 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 105 
                 uacuccagaa uguggca aucau 
                 mmu-miR-509-5p 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 106 
                 uaagugcgcg caug uauaugcg 
                 mmu-miR-467d 
                 1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 107 
                 ga ugugugug ua caug uacaua 
                 mmu-miR-466e-5p 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 108 
                   uagc ag cggg a acagu acugcag 
                 mmu-miR-503 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 109 
                 guaaagg cugg gcugaga 
                 mmu-miR-1971 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 110 
                 uucac cugg uccac uagc cg 
                 mmu-miR-412 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 111 
                 uucccuuugucauccuaugccu 
                 mmu-miR-204 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 112 
                 uccagcau cagu gauuuuguug 
                 mmu-miR-338-3p 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 113 
                 uacu cagu aa ggca   uug uucuu 
                 mmu-miR-201 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 114 
                 auuccuagaa auug uucacaau 
                 mmu-miR-384-3p 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 115 
                   acag gugagguucuug ggag cc 
                 mmu-miR-125a-3p 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 116 
                 uauacauacacgcacacauaaga 
                 mmu-miR-466c-3p 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 117 
                 uacugcaucaggaacuga cugg a 
                 mmu-miR-217 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 118 
                 aucguagaggaaaauccacgu 
                 mmu-miR-376a 
                 1 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 119 
                 a auug cacuu uagc aaugguga 
                 mmu-miR-367 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 120 
                   aggg gugcuauc ugug   auug ag 
                 mmu-miR-342-5p 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 121 
                 acuccauuuguuuugaugaugg 
                 mmu-miR-136 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 122 
                 uaaggugcaucuagugcuguuag 
                 mmu-miR-18b 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 123 
                 gaaagccac caugcugg guaaa 
                 mmu-miR-742 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 124 
                 aau ggcg ccacu aggg u ugug   
                 mmu-miR-652 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 125 
                 uu ugug ac cugg uccacua 
                 mmu-miR-758 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 126 
                 ccuaguaggugcu cagu aagugu 
                 mmu-miR-325* 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 127 
                 caacuagac ugug agcuucuag 
                 mmu-miR-708* 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 128 
                   cugggagaggg uuguuuacucc 
                 mmu-miR-30c-1* 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 129 
                 u acagu auagaugauguacu 
                 mmu-miR-144 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 130 
                 cggugggacuuguaguucgguc 
                 mmu-miR-1938 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 131 
                 guagu ggag a cuggugug gcua 
                 mmu-miR-1951 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 132 
                 acucaaaau ggag gcccuaucu 
                 mmu-miR-294* 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 133 
                 a ggag agagu uagc gcauuagu 
                 mmu-miR-882 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 134 
                 ccuguugaacaacugaacccaa 
                 mmu-miR-582-3p 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 135 
                 uauuuagaau ggca cuga ugug a 
                 mmu-miR-465a-5p 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 136 
                 aaacauucgcggugcacuucuu 
                 mmu-miR-543 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 137 
                   cugg ga ugug gauguuuacguc 
                 mmu-miR-30b* 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 138 
                 u ggca   gu gu auug u uag cugg   u 
                 mmu-miR-449a 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 139 
                 ccuucuucuucuuccugagaca 
                 mmu-miR-1903 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 140 
                 uaauacugu cugg uaaugccgu 
                 mmu-miR-429 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 141 
                 aaagugcuacuacuuuugagucu 
                 mmu-miR-295 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 142 
                 aaaccguuaccauuacugaguu 
                 mmu-miR-451 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 143 
                 uggauuucuc ugug aaucacua 
                 mmu-miR-876-5p 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 144 
                 ucugagu cccg gucgcgcgg 
                 mmu-miR-1199 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 145 
                 gaccu cugg auguu aggg acuga 
                 mmu-miR-1927 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 146 
                 uauguaacacgguccacuaacc 
                 mmu-miR-411* 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 147 
                 caucuua cugggca gc auug ga 
                 mmu-miR-200b* 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 148 
                 gaaguuguucgugguggauucg 
                 mmu-miR-382 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 149 
                 caaagugcucauagugcagguag 
                 mmu-miR-20b 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 150 
                 caucuuaccgg acagu g cugg a 
                 mmu-miR-200a* 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 151 
                 gcucgacu caug guuugaacca 
                 mmu-miR-434-5p 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 152 
                 cugcc cugg   cccg   aggg accga 
                 mmu-miR-874 
                 1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 153 
                 g ugug cggaaaugcuucugcua 
                 mmu-miR-147 
                 1 
                 0 
                 0 
                 −1 
                 1 
               
               
                   
               
               
                 154 
                 ucuu ggag uagau cagu g ggca g 
                 mmu-miR-432 
                 1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 155 
                 gcuuuaa caug ggguuaccugc 
                 mmu-miR-302c* 
                 1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 156 
                 caucccuug caug gu ggaggg   
                 mmu-miR-188-5p 
                 1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 157 
                 caacaaauc acagu cugccaua 
                 mmu-miR-7a* 
                 1 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 158 
                 acug cagu g agggca cuuguag 
                 mmu-miR-17* 
                 1 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 159 
                 cuauc cugg aaugcagcaauga 
                 mmu-miR-687 
                 1 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 160 
                 acuuuaa caug ggaaugcuuucu 
                 mmu-miR-302b* 
                 1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 161 
                 ugaggauc cuggggag aagaugc 
                 mmu-miR-1967 
                 1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 162 
                 u cagu uauc acagu gcugaugc 
                 mmu-miR-101a* 
                 1 
                 0 
                 −1 
                 −1 
                 1 
               
               
                   
               
               
                 163 
                 a aggg auucugauguuggucacacu 
                 mmu-miR-541 
                 1 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 164 
                 agguugccucauagugagcuugca 
                 mmu-miR-453 
                 1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 165 
                 caauguuucc acagu gcaucac 
                 mmu-miR-33* 
                 1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 166 
                 uggaauguaaggaag ugug ugg 
                 mmu-miR-206 
                 1 
                 −1 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 167 
                 aacauucaacgcugucggugagu 
                 mmu-miR-181a 
                 1 
                 −1 
                 1 
                 −1 
                 −1 
               
               
                   
               
               
                 168 
                 uuugguccccuucaaccagcua 
                 mmu-miR-133b 
                 1 
                 −1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 169 
                 uuugguccccuucaaccagcug 
                 mmu-miR-133a 
                 1 
                 −1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 170 
                 uagguaguuuccuguuguuggg 
                 mmu-miR-196b 
                 1 
                 −1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 171 
                 aacauucaaccugucggugagu 
                 mmu-miR-181c 
                 1 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 172 
                 gugcauuguaguugcauugca 
                 mmu-miR-33 
                 1 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 173 
                 uaggaaaguggaag cagu aagu 
                 mmu-miR-1958 
                 1 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 174 
                 aacauucauuguugucggugggu 
                 mmu-miR-181d 
                 1 
                 −1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 175 
                 uaguuuugcauaguugcacuac 
                 mmu-miR-19a* 
                 1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 176 
                 u ggca   gu gucu uag cugg   uugu 
                 mmu-miR-34a 
                 1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 177 
                 a ggca   gu guaau uagc ug auug u 
                 mmu-miR-34b-5p 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 178 
                 ugguagacuauggaacguagg 
                 mmu-miR-379 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 179 
                 cuccca caug c aggg uuugca 
                 mmu-miR-188-3p 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 180 
                 agucccaggaugcacugcagcuuuu 
                 mmu-miR-1955 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 181 
                 caaagugcuguucgugcagguag 
                 mmu-miR-93 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 182 
                 u acagu uguucaac cagu uacu 
                 mmu-miR-582-5p 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 183 
                 auaagacgaacaaaagguuugu 
                 mmu-miR-208b 
                 1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 184 
                 agucc aggg cugagucagcgga 
                 mmu-miR-1956 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 185 
                 gcc ggcgggag cccc agggag   
                 mmu-miR-2137 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 186 
                 ugg ugug agguugggccagga 
                 mmu-miR-1188 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 187 
                 aaga cgggag aagaga agggag   
                 mmu-miR-483 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 188 
                 a aggg aa cggg cuu ggcg gaau 
                 mmu-miR-2138 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 189 
                 ccguccugagguuguugagcu 
                 mmu-miR-676 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 190 
                 g aggg uugggu ggag gcucucc 
                 mmu-miR-296-3p 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 191 
                 gca agggagaggg uga agggag   
                 mmu-miR-1894-3p 
                 0 
                 1 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 192 
                 uccuucauuccacc ggag ucug 
                 mmu-miR-205 
                 0 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 193 
                 agcucggucugaggccccu cagu   
                 mmu-miR-423-3p 
                 0 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 194 
                 uacugagaauggg uagcagu ca 
                 mmu-miR-883b-5p 
                 0 
                 1 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 195 
                 ucaauggcugagguga ggca c 
                 mmu-miR-685 
                 0 
                 1 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 196 
                 cuagguaugguccc aggg aucc 
                 mmu-miR-331-5p 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 197 
                 agcuac auug ccagcuc 
                 mmu-miR-1928 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 198 
                 ucuccacccuccuucug 
                 mmu-miR-1952 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 199 
                 au acag aca caug cacacaca 
                 mmu-miR-466g 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 200 
                 agu ugugugugcaug uu caug u 
                 mmu-miR-669a 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 201 
                 cacgcu caug cacacacccaca 
                 mmu-miR-574-3p 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 202 
                 uguuugcagaggaaacugagac 
                 mmu-miR-452 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 203 
                 cucuccccuaccaccugccucu 
                 mmu-miR-1894-5p 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 204 
                 acuug aggggcaug aggau 
                 mmu-miR-327 
                 0 
                 1 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 205 
                 ucucac acag aaaucgca cccg u 
                 mmu-miR-342-3p 
                 0 
                 1 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 206 
                 aaa caug guuccgucaagcacc 
                 mmu-miR-218-1* 
                 0 
                 1 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 207 
                 cagauucgauucu aggg gaaua 
                 mmu-miR-10b* 
                 0 
                 1 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 208 
                 gagug cugg aauuaaa ggcaug   
                 mmu-miR-1186 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 209 
                 ua ugugugug ua caug uacaua 
                 mmu-miR-466a-5p 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 210 
                 uggugcggaa aggg ccc acagu   
                 mmu-miR-675-5p 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 211 
                 uaagugcgug caug uaua ugug   
                 mmu-miR-467c 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 212 
                 gaaugaguaacugcuagauccu 
                 mmu-miR-1194 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 213 
                 aguuu ugug ug caugugcaug u 
                 mmu-miR-669b 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 214 
                 cggcuacuucacaacacc aggg   
                 mmu-miR-138* 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 215 
                 g ggca ucugcuga caug gggg 
                 mmu-miR-680 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 216 
                 ug aggggca gagagcgagacuuu 
                 mmu-miR-423-5p 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 217 
                 ccacc acagu gucagacacuu 
                 mmu-miR-220 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 218 
                 uagu ugugugugcaug uuuaugu 
                 mmu-miR-6690 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 219 
                 ccag cugg gaagaac cagu ggc 
                 mmu-miR-763 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 220 
                 agaucagaaggugac ugug gcu 
                 mmu-miR-383 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 221 
                 acucaaa ugug g ggca cacuuc 
                 mmu-miR-295* 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 222 
                 ugagguugguguac ugugugug a 
                 mmu-miR-672 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 223 
                 uaugca agggca agcucucuuc 
                 mmu-miR-300 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 224 
                 ucagcugagguuccccucuguc 
                 mmu-miR-1190 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 225 
                 ugcauauacaca caug cauac 
                 mmu-miR-669i 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 226 
                 uugaaccccugaccuccu 
                 mmu-miR-2183 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 227 
                 ccugcuguaagc ugug uccuc 
                 mmu-miR-683 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 228 
                 cauacacacacacauacacac 
                 mmu-miR-466f-3p 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 229 
                 aucauagaggaacauccacuu 
                 mmu-miR-376b 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 230 
                 u ggagugug acaaugguguuug 
                 mmu-miR-122 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 231 
                 ggac ugug aggugacucuuggu 
                 mmu-miR-679 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 232 
                 a auug cacgguauccaucugua 
                 mmu-miR-363 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 233 
                 cauucucguuuccuucccu 
                 mmu-miR-698 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 234 
                 gcgacccauacuugguuucag 
                 mmu-miR-551b 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 235 
                 u ggag acgcggcccuguu ggag   
                 mmu-miR-139-3p 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 236 
                 ua ugug uuc cuggcugg cuugg 
                 mmu-miR-1198 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 237 
                 aacaauauc cugg ugcugagug 
                 mmu-miR-338-5p 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 238 
                 ggug ggag guggggug ggca   
                 mmu-miR-705 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 239 
                 ccaagucuugg ggag aguugag 
                 mmu-miR-710 
                 0 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 240 
                 acug cag ugug   agcacuucuag 
                 mmu-miR-20b* 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 241 
                 aacacacccagcuaaccuuuuu 
                 mmu-miR-329 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 242 
                 uug ggaggg uc cuggggag g 
                 mmu-miR-1982* 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 243 
                 cugaaaauguugccugaag 
                 mmu-miR-694 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 244 
                 agagg cugg ccgugaugaauuc 
                 mmu-miR-485 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 245 
                 augccuuuugcucugcacuca 
                 mmu-miR-511 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 246 
                 cagccacauccgaaaguuuuc 
                 mmu-miR-693-5p 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 247 
                 cc cccg a ggag gacga ggag ga 
                 mmu-miR-1895 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 248 
                 gcugaccccuaguc cagu gcuu 
                 mmu-miR-345-5p 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 249 
                 cugaagcucag aggg cucugau 
                 mmu-miR-127* 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 250 
                 aaucacuaacuccacugccauc 
                 mmu-miR-34b-3p 
                 0 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 251 
                 auucugcauuuu uagc aagcuc 
                 mmu-miR-544 
                 0 
                 1 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 252 
                 gcaggaacu ugug agucuccu 
                 mmu-miR-873 
                 0 
                 1 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 253 
                 c caguauug ac ugug cugcuga 
                 mmu-miR-16* 
                 0 
                 1 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 254 
                 cgaggugggau cccg aggccucucc 
                 mmu-miR-2143 
                 0 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 255 
                 uc cggg gcugaguuc ugug cacc 
                 mmu-miR-673-3p 
                 0 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 256 
                 cggcu cugg guc ugug ggga 
                 mmu-miR-760 
                 0 
                 0 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 257 
                 ggga cc cg     gggag agauguaag 
                 mmu-miR-711 
                 0 
                 0 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 258 
                 caucuuc cagu g cagu guugga 
                 mmu-miR-141* 
                 0 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 259 
                 ugaguauua caug gccaaucuc 
                 mmu-miR-496 
                 0 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 260 
                 uaugcauauacacg caug caa 
                 mmu-miR-669k 
                 0 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 261 
                 uaccaaguuuauuc ugug agaua 
                 mmu-miR-464 
                 0 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 262 
                 aaacaaacaa acag accaaauu 
                 mmu-miR-1192 
                 0 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 263 
                 ucggauccgucugagcuuggcu 
                 mmu-miR-127 
                 0 
                 0 
                 1 
                 0 
                 −1 
               
               
                   
               
               
                 264 
                 cac cagu cccaccacgcgguag 
                 mmu-miR-1905 
                 0 
                 0 
                 1 
                 −1 
                 0 
               
               
                   
               
               
                 265 
                 acucaaacuauggg ggca cuuu 
                 mmu-miR-290-5p 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 266 
                 ugaguucgaggccagccugcuca 
                 mmu-miR-1195 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 267 
                 uguccucuucucccuccuccca 
                 mmu-miR-877* 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 268 
                 uauacauacacacauacccaua 
                 mmu-miR-297b-3p 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 269 
                 ucucacccuauguucuccc acag   
                 mmu-miR-1982.1 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 270 
                 caucu uagcagu aucucccau 
                 mmu-miR-1941-3p 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 271 
                 guucugcuccu cuggagggag g 
                 mmu-miR-1904 
                 0 
                 0 
                 0 
                 1 
                 1 
               
               
                   
               
               
                 272 
                 aaugca cc cg     ggca aggauuug 
                 mmu-miR-501-3p 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 273 
                   cugg guguugacugaga ugug   
                 mmu-miR-2136 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 274 
                 ucaacucguucuguccggugag 
                 mmu-miR-1897-3p 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 275 
                 uaacugaccugc ugug aa cugg c 
                 mmu-miR-1936 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 276 
                 cuguugccacuaaccucaaccu 
                 mmu-miR-744* 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 277 
                 aauacauacacgcacacauaaga 
                 mmu-miR-466b-3- 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 3p 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 278 
                 aaagugccgccagguuuugagugu 
                 mmu-miR-292-3p 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 279 
                 ugggaaaguucucaggcuucug 
                 mmu-miR-1953 
                 0 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 280 
                 cug cagu c acagu gaagucug 
                 mmu-miR-682 
                 0 
                 0 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 281 
                 ua acagu cuc cagu cacggcca 
                 mmu-miR-212 
                 0 
                 0 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 282 
                 uagguuauccguguugccuucg 
                 mmu-miR-154 
                 0 
                 0 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 283 
                 auauacacacacacaccuaca 
                 mmu-miR-467f 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 284 
                 auacacacacacauacacacua 
                 mmu-miR-466i 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 285 
                 cuccuuca cc cg     ggcg guacc 
                 mmu-miR-712 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 286 
                 auauacauacacacaccuauau 
                 mmu-miR-467e* 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 287 
                 agacc cugg ucugcacucuauc 
                 mmu-miR-504 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 288 
                 gauc aggg ccuuucuaaguaga 
                 mmu-miR-465b-3p 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 289 
                 auauacauacacacaccuacac 
                 mmu-miR-467d* 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 290 
                   auug gggaugcuuugcauucau 
                 mmu-miR-450a-3p 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 291 
                 u cugg uccccugcuucguccucu 
                 mmu-miR-1934 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 292 
                 uauacauacacacacauauau 
                 mmu-miR-467g 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 293 
                 auaag ugug ag caug uauaugu 
                 mmu-miR-467e 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 294 
                 uaagugcuuc caug uuuugguga 
                 mmu-miR-302a 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 295 
                 ucugcaucuaaggauaugguca 
                 mmu-miR-1950 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 296 
                 aacauc cugg ucc uguggag a 
                 mmu-miR-697 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 297 
                   ugugugug cgua caug ua caug   
                 mmu-miR-466d-5p 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 298 
                 uaacugcaacaucucu cagu au 
                 mmu-miR-883b-3p 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 299 
                 aga caugug cucugcuccuag 
                 mmu-miR-704 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 300 
                 uauaaaua caug cacacauauu 
                 mmu-miR-4661 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 301 
                 agaggucuuggggccgaaac 
                 mmu-miR-2135 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 302 
                 uaaucucag cuggca ac ugug a 
                 mmu-miR-216a 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 303 
                 uguucaga cugg uguccauca 
                 mmu-miR-743b-5p 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 304 
                 uaagugcuuc caug uuuuaguag 
                 mmu-miR-302b 
                 0 
                 0 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 305 
                 ugacaccugccacccagcccaag 
                 mmu-miR-667 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 306 
                 ucu cugg gcc ugug ucuuaggc 
                 mmu-miR-330 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 307 
                 uuua ggca gagcacucgu acag   
                 mmu-miR-1948 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 308 
                 uaucuaguuggaugucaagaca 
                 mmu-miR-878-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 309 
                 uauacauacacgcacacauaaga 
                 mmu-miR-466a-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 310 
                 uccgagc cugg gucucccucuu 
                 mmu-miR-615-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 311 
                 aagcccuuaccccaaaaagcau 
                 mmu-miR-129-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 312 
                 agcugcgcugcuc cugg uaacugc 
                 mmu-miR-2139 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 313 
                 uagugguuuacaaaguaauuca 
                 mmu-miR-876-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 314 
                 uauaccu cagu uuuaucaggug 
                 mmu-miR-875-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 315 
                 auggu ggca c ggag uc 
                 mmu-miR-546 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 316 
                 acugcccuaagugcuccuucug 
                 mmu-miR-18a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 317 
                 uauuuagaauggugcugaucug 
                 mmu-miR-465b-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 318 
                 uggac ggag aacugaua aggg u 
                 mmu-miR-184 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 319 
                 agcgauggccgaaucugcuucc 
                 mmu-miR-1899 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 320 
                 uaggaca caug gucuacuucu 
                 mmu-miR-1197 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 321 
                 gaaagacaccaagcugaguaga 
                 mmu-miR-743a 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 322 
                 cgucuuacccag cagu guuugg 
                 mmu-miR-200c* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 323 
                 ucaagagcaauaacgaaaaaugu 
                 mmu-miR-335-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 324 
                 agu caug guguucggucuuaguuu 
                 mmu-miR-1933-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 325 
                 ugggacgagau caug aggccuuc 
                 mmu-miR-1963 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 326 
                 uguaaacaauuccua ggca augu 
                 mmu-miR-384-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 327 
                 ag auug   ggca uaggugacugaa 
                 mmu-miR-695 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 328 
                 uucuugga cuggcacugg ugagu 
                 mmu-miR-470 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 329 
                 acuuaaacgugguuguacuugc 
                 mmu-miR-302a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 330 
                 cacuag au ug     ug agcug cugg a 
                 mmu-miR-28* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 331 
                 uaagucacuagugguuccguu 
                 mmu-miR-224 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 332 
                 a agggagcugg cuca ggag agaguc 
                 mmu-miR-1966 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 333 
                 accgaccguugacuguaccuug 
                 mmu-miR-181a-2* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 334 
                 aagau ggag acuuuaa caug ggu 
                 mmu-miR-1969 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 335 
                 aaagugcuuccacuu ugug ugc 
                 mmu-miR-291a-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 336 
                 gguuguauuauc auug uccgag 
                 mmu-miR-374* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 337 
                 cagagagaua acagu cacaucu 
                 mmu-miR-881* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 338 
                 uauggcuuuucauuccua ugug a 
                 mmu-miR-135b 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 339 
                 ggcugcagcgugaucgccugcu 
                 mmu-miR-666-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 340 
                 aucaucgucucaaaugagucuu 
                 mmu-miR-136* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 341 
                 aggacgagc uagc ugagugcug 
                 mmu-miR-1947 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 342 
                 ugcugagagaag uagcagu uac 
                 mmu-miR-883a-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 343 
                 acucuuucccuguugcacuacu 
                 mmu-miR-130b* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 344 
                 caggucgucuugc aggg cuucu 
                 mmu-miR-431* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 345 
                 ca acagcagu cgaugggcuguc 
                 mmu-miR-21* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 346 
                 uacauacuucuuuacauucca 
                 mmu-miR-1-2-as 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 347 
                 acugcagagugagacccuguu 
                 mmu-miR-1954 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 348 
                 caggccauac ugug cugccuca 
                 mmu-miR-15a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 349 
                 uauggcuuuuuauuccua ugug a 
                 mmu-miR-135a 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 350 
                 gucuugggaaa cggg gugc 
                 mmu-miR-2134 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 351 
                 gauc aggg ccuuucuaaguaga 
                 mmu-miR-465a-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 352 
                 uacuca caug guugcuaauca 
                 mmu-miR-742* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 353 
                 uccgguucuc aggg cuccacc 
                 mmu-miR-671-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 354 
                 gcccuaaggugaauuuuuuggg 
                 mmu-miR-186* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 355 
                 agguua cccg agcaacuuugcau 
                 mmu-miR-409-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 356 
                 g caug acaccaca cugg guaga 
                 mmu-miR-878-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 357 
                 gaauguugcucggugaaccccu 
                 mmu-miR-409-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 358 
                 auuc cugg aaauacuguucuug 
                 mmu-miR-145* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 359 
                 uugcauauguaggaugucccau 
                 mmu-miR-448 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 360 
                 uacuccauccucucugaguaga 
                 mmu-miR-880 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 361 
                 ccuguucuccauuacuuggcuc 
                 mmu-miR-26b* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 362 
                 caagcucguguc ugug gguccg 
                 mmu-miR-99b* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 363 
                 c cagu gcuguuagaag aggg cu 
                 mmu-miR-1960 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 364 
                 ugccugucuacacuugc ugug c 
                 mmu-miR-214* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 365 
                 uc ggca acaagaaacugccuga 
                 mmu-miR-196a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 366 
                 cuauacaaucu auug ccuuccc 
                 mmu-let-7f* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 367 
                 gauc aggg ccuuucuaaguaga 
                 mmu-miR-465c-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 368 
                 auauacauacacacaccuacac 
                 mmu-miR-467a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 369 
                 cucucugaugguggguga ggag   
                 mmu-miR-1896 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 370 
                 u cagu aacaaagauucauccuu 
                 mmu-miR-802 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 371 
                 uacggugagccugucauuauuc 
                 mmu-miR-433* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 372 
                 uaccuaauuuguuguccaucau 
                 mmu-miR-463* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 373 
                 aaagugcuucccuuu ugug ugu 
                 mmu-miR-294 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 374 
                 cguguuc acag cggaccuugau 
                 mmu-miR-124* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 375 
                 uguaguguuuccuacuuuaugga 
                 mmu-miR-142-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 376 
                 cccagauaa uagc acucucaa 
                 mmu-miR-488* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 377 
                 guggauauuccuucuaugguua 
                 mmu-miR-376b* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 378 
                 ggggaug uagc u cagu   ggag   
                 mmu-miR-1959 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 379 
                 aaaucucugca ggca aa ugug a 
                 mmu-miR-216b 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 380 
                 cuauacaaccuacugccuuccc 
                 mmu-let-7b* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 381 
                 uauacauacacacauacccaua 
                 mmu-miR-297a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 382 
                 aucccugagugua ugug gugaa 
                 mmu-miR-670 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 383 
                 uggaagacu ugug auuuuguugu 
                 mmu-miR-7b 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 384 
                 u ugug u cagu uuaucaaac 
                 mmu-miR-599 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 385 
                 caaauucguaucu aggg gaaua 
                 mmu-miR-10a* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 386 
                 auauacauccacacaaacauau 
                 mmu-miR-669m 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 387 
                 uugaagagagguuauccuuugu 
                 mmu-miR-300* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 388 
                 ag cugg ugu ugug aaucaggccg 
                 mmu-miR-138 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 389 
                 aaaag cugg guugag aggg cga 
                 mmu-miR-320 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 390 
                 ug cggg gcu aggg cua acag ca 
                 mmu-miR-744 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 391 
                 cucag acag agauaccuucucu 
                 mmu-miR-717 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 392 
                 uauacauacacacauacccaua 
                 mmu-miR-297c* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 393 
                 ugu cagu uugucaaauacccca 
                 mmu-miR-223 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 394 
                 cuguaugcccuaaccgcu cagu   
                 mmu-miR-675-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 395 
                 uggaagacuagugauuuuguugu 
                 mmu-miR-7a 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 396 
                 gcuuauggcuucaagcuuucgg 
                 mmu-miR-879* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 397 
                 gcccu aggg acu cagu u cugg u 
                 mmu-miR-146b* 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 398 
                 ucccuga ggag cccuuugagccug 
                 mmu-miR-351 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 399 
                 u auug cacauuacuaaguugca 
                 mmu-miR-32 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 400 
                 agugccgcagaguuuguagugu 
                 mmu-miR-293 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 401 
                 aauccuuugucc cugg gugaaa 
                 mmu-miR-501-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 402 
                 uaacugca acag cucu cagu au 
                 mmu-miR-883a-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 403 
                 aucucggcu acag aaaaauguu 
                 mmu-miR-719 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 404 
                 caaagaauucuccuuuugggcu 
                 mmu-miR-186 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 405 
                 uucaccaccuucuccacccagc 
                 mmu-miR-197 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 406 
                 cc cagu guucagacuaccuguuc 
                 mmu-miR-199a-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 407 
                 uaacacugu cugg uaacgaugu 
                 mmu-miR-200a 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 408 
                 uaauacugc cggg uaaugaugga 
                 mmu-miR-200c 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 409 
                 agaggua uagc g caug ggaaga 
                 mmu-miR-202-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 410 
                 uuccuaugcauauacuucuuu 
                 mmu-miR-202-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 411 
                 gugaaauguuuaggaccacuag 
                 mmu-miR-203 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 412 
                   aggg cccccccucaauccugu 
                 mmu-miR-296-5p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 413 
                 ugagcgccucggcg acag agccg 
                 mmu-miR-339-3p 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 414 
                 ugauagacaccauauaagguag 
                 mmu-miR-463 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 415 
                 ucgcaggcgacuacuuauuc 
                 mmu-miR-688 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 416 
                 gcagagugcaaacaauuuugac 
                 mmu-miR-759 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 417 
                 gggg cugg ggc cggg   acag agc 
                 mmu-miR-762 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 418 
                 gaucaaagu ggag gcccucucc 
                 mmu-miR-291b-5p 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 419 
                 ugguuuaccgucccacauacau 
                 mmu-miR-299* 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 420 
                 ccucccacacccaaggcuugca 
                 mmu-miR-532-3p 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 421 
                 gcugcacuuggauuucguuccc 
                 mmu-miR-191* 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 422 
                 uaa cagu cu acag c caug gucg 
                 mmu-miR-132 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 423 
                 ugaacu auugcaguagc cuccu 
                 mmu-miR-872* 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 424 
                 uaauacugc cugg uaaugauga 
                 mmu-miR-200b 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 425 
                 uagguca cccg uuuuacuauc 
                 mmu-miR-1193 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 426 
                 cgacg aggg ccggucggucgc 
                 mmu-miR-714 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 427 
                 auuccugaagaga ggca gaaaa 
                 mmu-miR-691 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 428 
                 agaucgaccguguuauauucgc 
                 mmu-miR-369-5p 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 429 
                 au cggg aaugucguguccgcc 
                 mmu-miR-425* 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 430 
                 uaugucugcugaccaucaccuu 
                 mmu-miR-654-3p 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 431 
                 cacg cggg aaccgaguccacc 
                 mmu-miR-700 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 432 
                 ccgacuu cugg gcuccggcuuu 
                 mmu-miR-1964 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 433 
                 gguagauucuccuucuaugagu 
                 mmu-miR-376a* 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 434 
                 uacgucaucgucgucaucguua 
                 mmu-miR-598 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 435 
                 aauaaua caug guugaucuuu 
                 mmu-miR-369-3p 
                 0 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 436 
                 ugguaagcugcagaa caugug u 
                 mmu-miR-654-5p 
                 0 
                 0 
                 0 
                 −1 
                 1 
               
               
                   
               
               
                 437 
                 cuuuuugcggu cugg gcuugc 
                 mmu-miR-129-5p 
                 0 
                 0 
                 0 
                 −1 
                 1 
               
               
                   
               
               
                 438 
                 cugcgcaagcuacugccuugcu 
                 mmu-let-7i* 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 439 
                 acaagucagguucuugggaccu 
                 mmu-miR-125b* 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 440 
                 uaugcauauacaca caug caca 
                 mmu-miR-669h-3p 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 441 
                 uggaauguaaagaaguauguau 
                 mmu-miR−1 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 442 
                 ucagaugucuucau cugg uug 
                 mmu-miR-1942 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 443 
                 aug caug gguguauaguugagugc 
                 mmu-miR-669h-5p 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 444 
                   cagu cuuacuaug uagc ccua 
                 mmu-miR-1191 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 445 
                 augaccuaugauuug acag ac 
                 mmu-miR-215 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 446 
                 uuuug cagu auguuccugaaua 
                 mmu-miR-450b-5p 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 447 
                 acucuacaaccuuaggacuugc 
                 mmu-miR-676* 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 448 
                 ccugaaaauacugaggcuaug 
                 mmu-miR-875-3p 
                 0 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 449 
                 g cagu cca cgggca uauacac 
                 mmu-miR-455 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 450 
                 c ugug cg ugug   acag cggcuga 
                 mmu-miR-210 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 451 
                 aaucauacacgguugaccuauu 
                 mmu-miR-154* 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 452 
                 augguugaccauagaa caug cg 
                 mmu-miR-380-5p 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 453 
                 ugucu ugugugugcaug uucau 
                 mmu-miR-669e 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 454 
                 acugcugagc uagc acuu cccg   
                 mmu-miR-93* 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 455 
                 cuugguacaucuuugagugag 
                 mmu-miR-547 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 456 
                   au ug     ug ucaauaugcgaugaugu 
                 mmu-miR-592 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 457 
                   cagu gcaauuaaa aggg ggaa 
                 mmu-miR-721 
                 0 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 458 
                 cucac cuggagcaug uuuucu 
                 mmu-miR-1983 
                 0 
                 0 
                 −1 
                 1 
                 0 
               
               
                   
               
               
                 459 
                 uauacauacacgcacacauag 
                 mmu-miR-466d-3p 
                 0 
                 0 
                 −1 
                 1 
                 0 
               
               
                   
               
               
                 460 
                 gcg ugug cuugc ugug gg 
                 mmu-miR-696 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 461 
                 agc cggg     ca gu ggu ggca cacacuu 
                 mmu-miR-1946a 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 uu 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 462 
                 u ggag agaaa gg     ca gu uccuga 
                 mmu-miR-185 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 463 
                 auauacauacacacaccaacac 
                 mmu-miR-467b* 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 464 
                 aguggggaacccuuc caug agg 
                 mmu-miR-491 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 465 
                 a ggca gagg cugg cggaucucu 
                 mmu-miR-1935 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 466 
                 agagcu uagc ug auug gugaac 
                 mmu-miR-27b* 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
               
               
                 467 
                 gc cggg     ca gu ggu ggcacaug   
                 mmu-miR-1946b 
                 0 
                 0 
                 −1 
                 0 
                 1 
               
               
                   
                 cuuuu 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 468 
                   auug ggaacauuuug caug cau 
                 mmu-miR-450b-3p 
                 0 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 469 
                 acucaaac ugug ugacauuuug 
                 mmu-miR-293* 
                 0 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 470 
                   aggg cu uagc ugcu ugug agca 
                 mmu-miR-27a* 
                 0 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 471 
                 gaaagacau caug cugaauaga 
                 mmu-miR-743b-3p 
                 0 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 472 
                 agugguucuug acagu ucaaca 
                 mmu-miR-203* 
                 0 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 473 
                 aaaguucugagacacuccgacu 
                 mmu-miR-148a* 
                 0 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 474 
                 uugaaaggcuguuucuugguc 
                 mmu-miR-488 
                 0 
                 0 
                 −1 
                 −1 
                 1 
               
               
                   
               
               
                 475 
                 ugcauauacuca caug caaaca 
                 mmu-miR-669j 
                 0 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 476 
                 ucauucacggacaacacuuuuu 
                 mmu-miR-382* 
                 0 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 477 
                 acu ugugugugcaug uauaugu 
                 mmu-miR-669d 
                 0 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 478 
                 accuccauaguaccugcagcgu 
                 mmu-miR-1930 
                 0 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 479 
                 uccgucu cagu uacuuua uagc   
                 mmu-miR-340-3p 
                 0 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 480 
                 u uagc cgcugaaauagaugga 
                 mmu-miR-701 
                 0 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 481 
                 cauuauuacuuuugguacgcg 
                 mmu-miR-126-5p 
                 0 
                 −1 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 482 
                 a ggca agaug cuggca   uagc ug 
                 mmu-miR-31 
                 0 
                 −1 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 483 
                 ugagaugaagcacug uagc uc 
                 mmu-miR-143 
                 0 
                 −1 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 484 
                 uagguaguuu caug uuguuggg 
                 mmu-miR-196a 
                 0 
                 −1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 485 
                 g cugg uuucauauggugguuua 
                 mmu-miR-29b* 
                 0 
                 −1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 486 
                 u cugg cuccgugucuucacuccc 
                 mmu-miR-149 
                 0 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 487 
                 uc acagu gaaccggucucuuu 
                 mmu-miR-128 
                 0 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 488 
                 agagaaacccugucucaaaaaa 
                 mmu-miR-706 
                 0 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 489 
                 uugcauagucacaaaagugauc 
                 mmu-miR-153 
                 0 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 490 
                 ugggucuuug cgggca agauga 
                 mmu-miR-193* 
                 0 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 491 
                 aaa caug aagcgcugcaacac 
                 mmu-miR-322* 
                 0 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 492 
                 ucuuugguuauc uagc uguauga 
                 mmu-miR-9 
                 0 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 493 
                 ugauauguuugau auug gguu 
                 mmu-miR-190b 
                 0 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 494 
                 uuuguucguucggcucgcguga 
                 mmu-miR-375 
                 0 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 495 
                 aggugggg auug gu ggca uuac 
                 mmu-miR-92a* 
                 0 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 496 
                 acugcauuacgagcacuuaaag 
                 mmu-miR-20a* 
                 0 
                 −1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 497 
                 g cugg uaaaauggaaccaaau 
                 mmu-miR-133a* 
                 0 
                 −1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 498 
                 aacacaccuguucaaggauuca 
                 mmu-miR-362-3p 
                 0 
                 −1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 499 
                 uaaagugcuuauagugcagguag 
                 mmu-miR-20a 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 500 
                 caaagugcua acagu gcagguag 
                 mmu-miR-106a 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 501 
                   caug ccuugaguguaggaccgu 
                 mmu-miR-532-5p 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 502 
                 cgaaucauuauuugcugcucua 
                 mmu-miR-15b* 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 503 
                 caacggaaucccaaaagcagcug 
                 mmu-miR-191 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 504 
                 aacauuc auug cugucggugggu 
                 mmu-miR-181b 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 505 
                 ucguaccgugaguaauaaugcg 
                 mmu-miR-126-3p 
                 0 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 506 
                 uaaggugcaucuagugcagauag 
                 mmu-miR-18a 
                 0 
                 −1 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 507 
                 aguucuu cagu   ggca agcuuua 
                 mmu-miR-22* 
                 0 
                 −1 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 508 
                   cagu gcaauagu auug ucaaagc 
                 mmu-miR-301a 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 509 
                   cagu gcaauggu auug ucaaagc 
                 mmu-miR-301b 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 510 
                 caaagugcuu acagu gcagguag 
                 mmu-miR-17 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 511 
                 accaucgaccguug auug uacc 
                 mmu-miR-181a-1* 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 512 
                 aauccuuggaaccuagg ugug aau 
                 mmu-miR-362-5p 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 513 
                 uuaagacuug cagu gauguuu 
                 mmu-miR-499 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 514 
                 acugauuucuuuugguguucag 
                 mmu-miR-29a* 
                 0 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 515 
                 aa cugg cccacaaagu cccg cu 
                 mmu-miR-193b 
                 −1 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 516 
                 ac cggg ugcuguaggcuuu 
                 mmu-miR-2142 
                 −1 
                 1 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 517 
                 guaga ggag auggcgc aggg   
                 mmu-miR-877 
                 −1 
                 1 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 518 
                 cgcauccccu agggc     a uug gugu 
                 mmu-miR-324-5p 
                 −1 
                 1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 519 
                 aucucuuugagcgccucacuc 
                 mmu-miR-692 
                 −1 
                 1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 520 
                   acag ca ggc     a cagaca g     g     ca gu   
                 mmu-miR-214 
                 −1 
                 1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 521 
                 aa cugg ccuacaaagucc cagu   
                 mmu-miR-193 
                 −1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 522 
                 caucaaagu ggag gcccucucu 
                 mmu-miR-291a-5p 
                 −1 
                 1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 523 
                 agc aggg u cggg c cugg uu 
                 mmu-miR-2145 
                 −1 
                 1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 524 
                 agcaccacgugu cugg gccacg 
                 mmu-miR-770-5p 
                 −1 
                 1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 525 
                 cauauacauacacacacacguau 
                 mmu-miR-669f 
                 −1 
                 1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 526 
                 gugagga cuggggag gu ggag   
                 mmu-miR-1224 
                 −1 
                 0 
                 1 
                 1 
                 1 
               
               
                   
               
               
                 527 
                 auuugggga cgggagggag gau 
                 mmu-miR-1892 
                 −1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 528 
                 aagc cggg ccguaguggcgca 
                 mmu-miR-1965 
                 −1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 529 
                 gg cggg uguugacgcgaug 
                 mmu-miR-2132 
                 −1 
                 0 
                 1 
                 1 
                 0 
               
               
                   
               
               
                 530 
                 aa ggag cuuacaauc uag c     ugg g 
                 mmu-miR-708 
                 −1 
                 0 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 531 
                   cagu gcaaugaugaa agggca u 
                 mmu-miR-130b 
                 −1 
                 0 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 532 
                 uaguagaccgua uagc guacg 
                 mmu-miR-411 
                 −1 
                 0 
                 1 
                 1 
                 −1 
               
               
                   
               
               
                 533 
                 a ggag gugucagaaaaguu 
                 mmu-miR-2141 
                 −1 
                 0 
                 1 
                 0 
                 1 
               
               
                   
               
               
                 534 
                 cuuccg cccg gc cggg ugucg 
                 mmu-miR-718 
                 −1 
                 0 
                 1 
                 0 
                 0 
               
               
                   
               
               
                 535 
                   cugg cccucucugcccuuccgu 
                 mmu-miR-328 
                 −1 
                 0 
                 1 
                 0 
                 −1 
               
               
                   
               
               
                 536 
                   ugug aguuguuccucac cugg a 
                 mmu-miR-804 
                 −1 
                 0 
                 1 
                 0 
                 −1 
               
               
                   
               
               
                 537 
                   ggaggca ga ggcaggag ga 
                 mmu-miR-709 
                 −1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 538 
                 augca agggcugg ugcgauggc 
                 mmu-miR-1931 
                 −1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 539 
                 guaaagg cugg gcuuagacguggc 
                 mmu-miR-1981 
                 −1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 540 
                 gagugccuagugggccacuuuuggu 
                 mmu-miR-2144 
                 −1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 541 
                 uau aggg   auu g     gag ccguggcg 
                 mmu-miR-135a* 
                 −1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 542 
                 uauacauacacgcacacauaaga 
                 mmu-miR-466b-3p 
                 −1 
                 0 
                 0 
                 1 
                 0 
               
               
                   
               
               
                 543 
                 aggugguccguggcgcguucgc 
                 mmu-miR-323-5p 
                 −1 
                 0 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 544 
                 ugagguaguagguuguaugguu 
                 mmu-let-7c 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 545 
                 ugagguaguaggu ugug ugguu 
                 mmu-let-7b 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 546 
                 a cugg acuu ggag ucagaagg 
                 mmu-miR-378 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 547 
                 aggugcagaucuugguggu 
                 mmu-miR-2140 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 548 
                 gu ggag a aggg uuc caugug   
                 mmu-miR-2146 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 549 
                 ucu acagu gcacgugucuccag 
                 mmu-miR-139-5p 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 550 
                 uau ggcacugg uagaauucacu 
                 mmu-miR-183 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 551 
                 cuauacaaucuacugucuuucc 
                 mmu-let-7c-2* 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 552 
                 ugaaacauaca cggg aaaccuc 
                 mmu-miR-494 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 553 
                 uaaugccccuaaaaauccuuau 
                 mmu-miR-365 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 554 
                 uauuuagaauggcgcugaucug 
                 mmu-miR-465c-5p 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 555 
                 guaagugccug caug uauaug 
                 mmu-miR-467b 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 556 
                 cuc acag cu cugg uccuu ggag   
                 mmu-miR-673-5p 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 557 
                   ggag aaauuauccuugg ugug u 
                 mmu-miR-539 
                 −1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 558 
                 u auug cacuugu cccg gccug 
                 mmu-miR-92a 
                 −1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 559 
                 cuagacugaggcuccuugagg 
                 mmu-miR-151-3p 
                 −1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 560 
                 ugucacucggcucggcccacuacc 
                 mmu-miR-668 
                 −1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 561 
                   ugug a cugg uugaccag aggg g 
                 mmu-miR-134 
                 −1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 562 
                 u auug cacucgu cccg gccucc 
                 mmu-miR-92b 
                 −1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 563 
                 aaucacuaaccac acag ccagg 
                 mmu-miR-34c* 
                 −1 
                 0 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 564 
                 uauucagauuagugc cagu   caug   
                 mmu-miR-871 
                 −1 
                 0 
                 0 
                 −1 
                 1 
               
               
                   
               
               
                 565 
                 gu cccg   cggg g cccg aagcguu 
                 mmu-miR-2133 
                 −1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 566 
                 ugcac caug guugucugagca 
                 mmu-miR-767 
                 −1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 567 
                 auaaagcuagauaaccgaaagu 
                 mmu-miR-9* 
                 −1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 568 
                 ugagagaugccauucuauguaga 
                 mmu-miR-741 
                 −1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 569 
                 uucuaggacuuuauagagcagag 
                 mmu-miR-1929 
                 −1 
                 0 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 570 
                 ucgauucccugccaaugcac 
                 mmu-miR-1939 
                 −1 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 571 
                 gccc cugg gccuauccuagaa 
                 mmu-miR-331-3p 
                 −1 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 572 
                 cugaccuauga auugacag cc 
                 mmu-miR-192 
                 −1 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 573 
                 aaugacacgaucacu cccg uuga 
                 mmu-miR-425 
                 −1 
                 0 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 574 
                 uaagugccug caug uauaugcg 
                 mmu-miR-467a 
                 −1 
                 0 
                 −1 
                 1 
                 0 
               
               
                   
               
               
                 575 
                 agagg cuggcacugg gacacau 
                 mmu-miR-1962 
                 −1 
                 0 
                 −1 
                 1 
                 −1 
               
               
                   
               
               
                 576 
                 cuauacgaccugcugccuuucu 
                 mmu-let-7d* 
                 −1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 577 
                 gcaaagc ac ag     gg ccugcagaga 
                 mmu-miR-330* 
                 −1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 578 
                 uuaucagaaucucc aggg guac 
                 mmu-miR-361 
                 −1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 579 
                 cuccugacuccaggucc ugug u 
                 mmu-miR-378* 
                 −1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 580 
                 acucaaa cugg gggcucuuuug 
                 mmu-miR-292-5p 
                 −1 
                 0 
                 −1 
                 0 
                 0 
               
               
                   
               
               
                 581 
                 ccaggaccau cag u     gug acuau 
                 mmu-miR-1933-3p 
                 −1 
                 0 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 582 
                 cuuuggau ggag aaag aggg gg 
                 mmu-miR-1897-5p 
                 −1 
                 0 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 583 
                 ugc auug ua ugug uuga caug au 
                 mmu-miR-669g 
                 −1 
                 0 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 584 
                 uuu ggca augguagaacucacaccg 
                 mmu-miR-182 
                 −1 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 585 
                   cugggag aaggcuguuuacucu 
                 mmu-miR-30c-2* 
                 −1 
                 0 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 586 
                 aucucg cugg ggccucca 
                 mmu-miR-720 
                 −1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 587 
                 ccgcac ugug gguacuugcugc 
                 mmu-miR-106b* 
                 −1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 588 
                 ggccgcccucu cugg uccuuca 
                 mmu-miR-1900 
                 −1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 589 
                 cagcagcacac ugug guuugua 
                 mmu-miR-497 
                 −1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 590 
                 ucccuguccucca ggag cucacg 
                 mmu-miR-339-5p 
                 −1 
                 0 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 591 
                 ccgcucguacu cc cg     gg ggucc 
                 mmu-miR-1901 
                 −1 
                 −1 
                 1 
                 −1 
                 −1 
               
               
                   
               
               
                 592 
                 guc cagu uuucccaggaaucccu 
                 mmu-miR-145 
                 −1 
                 −1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 593 
                 aaaggcuaggcucacaaccaaa 
                 mmu-miR-690 
                 −1 
                 −1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 594 
                 gugaauuaccga aggg ccauaa 
                 mmu-miR-183* 
                 −1 
                 −1 
                 0 
                 1 
                 −1 
               
               
                   
               
               
                 595 
                 aac ugug ucuuuucugaauaga 
                 mmu-miR-881 
                 −1 
                 −1 
                 0 
                 0 
                 1 
               
               
                   
               
               
                 596 
                 agagguaguagguugcauaguu 
                 mmu-let-7d 
                 −1 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 597 
                 ugagguaguagguuguauaguu 
                 mmu-let-7a 
                 −1 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 598 
                 guugcgg acag cgcuaggucgg 
                 mmu-miR-1932 
                 −1 
                 −1 
                 0 
                 0 
                 0 
               
               
                   
               
               
                 599 
                 cc cagu guuuagacuaccuguuc 
                 mmu-miR-199b* 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 600 
                 uucaaguaauucaggauaggu 
                 mmu-miR-26b 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 601 
                 auca acag acauua auug ggcgc 
                 mmu-miR-421 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 602 
                 ucga ggag cuc acagu cuagu 
                 mmu-miR-151-5p 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 603 
                   uagc agcacau caug guuuaca 
                 mmu-miR-15b 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 604 
                 u ugug cuugaucuaac caug u 
                 mmu-miR-218 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 605 
                 gugccuacugagcugauau cagu   
                 mmu-miR-24-1* 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 606 
                 c acag cucccaucucagaacaa 
                 mmu-miR-674* 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 607 
                 uauucauuuacuccccagccua 
                 mmu-miR-664 
                 −1 
                 −1 
                 0 
                 0 
                 −1 
               
               
                   
               
               
                 608 
                 ugagguaguag auug uauaguu 
                 mmu-let-7f 
                 −1 
                 −1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 609 
                 ugagguaguaaguugu auug uu 
                 mmu-miR-98 
                 −1 
                 −1 
                 0 
                 −1 
                 0 
               
               
                   
               
               
                 610 
                 aa cccg uagauccgaucu ugug   
                 mmu-miR-99a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 611 
                 uuc acagu ggcuaaguuccgc 
                 mmu-miR-27a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 612 
                 aucac auug cc aggg auuucc 
                 mmu-miR-23a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 613 
                 uucaaguaauccaggauaggcu 
                 mmu-miR-26a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 614 
                   uagc accaucugaaaucgguua 
                 mmu-miR-29a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 615 
                 uacccuguagauccgaauu ugug   
                 mmu-miR-10a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 616 
                 ucccugagacccuaacu ugug a 
                 mmu-miR-125b-5p 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 617 
                 ucaggcu cagu ccccu cccg au 
                 mmu-miR-484 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 618 
                   uagc accauuugaaaucgguua 
                 mmu-miR-29c 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 619 
                 aa cccg uagauccgaacu ugug   
                 mmu-miR-100 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 620 
                   acagu agucugcac auug guua 
                 mmu-miR-199a-3p 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 621 
                 aagcugc cagu ugaagaacugu 
                 mmu-miR-22 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 622 
                   uagc uuaucagacugauguuga 
                 mmu-miR-21 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 623 
                 agcagc auug u ac ag     gg cuauca 
                 mmu-miR-107 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 624 
                 ucccugagacccuuuaacc ugug a 
                 mmu-miR-125a-5p 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 625 
                 uacccuguagaaccgaauu ugug   
                 mmu-miR-10b 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 626 
                 ucaggucccuguucaggcgcca 
                 mmu-miR-1274a 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 627 
                 aa ggag cuc acagu cu auug ag 
                 mmu-miR-28 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 628 
                 c auug cacuugucucggucuga 
                 mmu-miR-25 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 629 
                 uggcu cagu ucagcagga acag   
                 mmu-miR-24 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 630 
                   acagu agucugcac auug guua 
                 mmu-miR-199b 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 631 
                 ugagguaguaguuugu acagu u 
                 mmu-let-7g 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 632 
                 ugaggua ggag guuguauaguu 
                 mmu-let-7e 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 633 
                 agcuac auug ucug cugg guuuc 
                 mmu-miR-221 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 634 
                 acgccacauuucccacgccgcg 
                 mmu-miR-2182 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 635 
                 uuuugcga ugug uuccuaauau 
                 mmu-miR-450a-5p 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 636 
                 agcuacau cugg cua cugg gu 
                 mmu-miR-222 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 637 
                   uagc accauuugaaau cagu guu 
                 mmu-miR-29b 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 638 
                 uucacaaagcccauacacuuuc 
                 mmu-miR-350 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 639 
                 aaaaccuucagaaggaaagaa 
                 mmu-miR-703 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 640 
                 auauaauacaaccugcuaagug 
                 mmu-miR-374 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 641 
                 ugcuaugccaacau auug ccauc 
                 mmu-miR-31* 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 642 
                 cacauuacacggucgaccucu 
                 mmu-miR-323-3p 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 643 
                 cuauaccaggaugucagcauaguu 
                 mmu-miR-1949 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 644 
                 aac cagu accuuucugagaaga 
                 mmu-miR-470* 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 645 
                 uuaaugcua au ug     ug au aggg gu 
                 mmu-miR-155 
                 −1 
                 −1 
                 0 
                 −1 
                 −1 
               
               
                   
               
               
                 646 
                 uauacauacacgcacacauaaga 
                 mmu-miR-466e-3p 
                 −1 
                 −1 
                 −1 
                 1 
                 −1 
               
               
                   
               
               
                 647 
                 u cagu g caug   acag aacuugg 
                 mmu-miR-152 
                 −1 
                 −1 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 648 
                 a gg     ca gu guagu uagc ug auug c 
                 mmu-miR-34c 
                 −1 
                 −1 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 649 
                 ugcccacccuuuac cccg cuc 
                 mmu-miR-702 
                 −1 
                 −1 
                 −1 
                 0 
                 −1 
               
               
                   
               
               
                 650 
                 uuu ggca c uagc acauuuuugcu 
                 mmu-miR-96 
                 −1 
                 −1 
                 −1 
                 −1 
                 1 
               
               
                   
               
               
                 651 
                   ugug   acagauug auaacugaaa 
                 mmu-miR-542-3p 
                 −1 
                 −1 
                 −1 
                 −1 
                 0 
               
               
                   
               
               
                 652 
                 ga auug aucaggacau aggg   
                 mmu-miR-805 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 653 
                 cuc ugug cugaaugucaaguu 
                 mmu-miR-1944 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
                 cugauu 
                   
                   
                   
                   
                   
                   
               
               
                   
               
               
                 654 
                 uu cagu gaugau uagc uucuga 
                 mmu-miR-677 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 655 
                 cuccgugcacacc cccg cgug 
                 mmu-miR-715 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 656 
                 agaccuacuuaucuacca acag c 
                 mmu-miR-1839-3p 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 657 
                   ugug caaauc caug caaaacuga 
                 mmu-miR-19b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 658 
                 u cagu gcacu acag aacuuugu 
                 mmu-miR-148a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 659 
                 aau cccg gacgagccccca 
                 mmu-miR-1937a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 660 
                 u cagu gcauc acag aacuuugu 
                 mmu-miR-148b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 661 
                 u acagu ac ugug auaacugaa 
                 mmu-miR-101a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 662 
                 aucac auug cc aggg auuacc 
                 mmu-miR-23b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 663 
                 aagguuacuuguuaguucagg 
                 mmu-miR-872 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 664 
                 ca cccg uagaaccgaccuugcg 
                 mmu-miR-99b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 665 
                   ugug caaaucuaugcaaaacuga 
                 mmu-miR-19a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 666 
                   cagu gcaauguuaaa agggca u 
                 mmu-miR-130a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 667 
                 au cccg gacgagccccca 
                 mmu-miR-1937b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 668 
                 cuauacaaucuacugucuuucc 
                 mmu-let-7a* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 669 
                 uguaaacauccuacacucagcu 
                 mmu-miR-30b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 670 
                   uagc agcacguaaau auug gcg 
                 mmu-miR-16 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 671 
                 uguaaacauc cccg a cugg aag 
                 mmu-miR-30d 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 672 
                 uguaaacauccucga cugg aag 
                 mmu-miR-30a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 673 
                 u acagu ac ugug a uagc ugaa 
                 mmu-miR-101b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 674 
                 uguaaacauccuacacucucagc 
                 mmu-miR-30c 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 675 
                 cuuu cagu cggauguuu acag c 
                 mmu-miR-30e* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 676 
                 uuc acagu ggcuaaguucugc 
                 mmu-miR-27b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 677 
                 uguaaacauccuuga cugg aag 
                 mmu-miR-30e 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 678 
                 agcagc auug u ac ag     gg cuauga 
                 mmu-miR-103 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 679 
                   uagc agcacauaaugguu ugug   
                 mmu-miR-15a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 680 
                 ugua acag caacuc caugug ga 
                 mmu-miR-194 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 681 
                 ugagaacugaauuccauaggcu 
                 mmu-miR-146b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 682 
                 ugagguaguaguu ugug cuguu 
                 mmu-let-7i 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 683 
                 au cccg gaagagccccca 
                 mmu-miR-1937c 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 684 
                 uacc ac ag     gg uagaaccacgg 
                 mmu-miR-140* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 685 
                   cagu gguuuuacccuaugguag 
                 mmu-miR-140 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 686 
                 aagguagauaga acag gucuug 
                 mmu-miR-1839-5p 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 687 
                   uagc agc acag aaau auug gc 
                 mmu-miR-195 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 688 
                 cuuu cagu cggauguuugcagc 
                 mmu-miR-30a* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 689 
                 uaaagugcug acagu gcagau 
                 mmu-miR-106b 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 690 
                 cagcagcaauu caug uuuugga 
                 mmu-miR-322 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 691 
                 aguuuucccuucaagucaa 
                 mmu-miR-684 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 692 
                 guguugaaacaaucucuacug 
                 mmu-miR-653 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 693 
                 gccug cugg gguggaac cugg u 
                 mmu-miR-370 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 694 
                 ua ugug ccuuuggacuacaucg 
                 mmu-miR-455* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 695 
                 ugauauguuugauauauuaggu 
                 mmu-miR-190 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 696 
                 cuguacaaccuuc uagc uuucc 
                 mmu-let-7c-1* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 697 
                 ucucccuu caugug cccaga 
                 mmu-miR-343 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 698 
                 ugagaacugaauuc caug gguu 
                 mmu-miR-146a 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 699 
                 ug auug uccaaacgcaauucu 
                 mmu-miR-219 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 700 
                 gugccuacugagcugaa acagu   
                 mmu-miR-24-2* 
                 −1 
                 −1 
                 −1 
                 −1 
                 −1 
               
               
                   
               
               
                 701 
                 AGGCAGU   GUG   UGUAGCUGAUUGC 
                 miR-34c-5p- 
                 Not 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 UGUG 
                 availa 
                   
                   
                   
                   
               
               
                   
                   
                   
                 ble 
                   
                   
                   
                   
               
               
                   
                   
                   
                 (N/A) 
                   
                   
                   
                   
               
               
                   
               
               
                 702 
                 AGGCAGUGUAGUUAGCU   C   AU   G   GC 
                 miR-34c-5p- 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 CAUG 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 703 
                 AGGCAGUGUAGUUAGC   G   G   GAG   GC 
                 miR-34c-5p- 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 CGGGAG 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 704 
                 GCAGCUUUCAGAU   C   UGGCUGUAA 
                 miR-693-3p- 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                   
                 mut 
               
               
                   
               
            
           
         
       
     
     As shown in  FIG. 4A, 6  main nucleotide motifs in the mature miRNAs were identified that were significantly more abundant in the miRNAs that had preferential sorting to exosomes. All values for individual cell types indicates the percentage of miRNAs in the exosome fraction of that cell type that contained a given motif. The “total” value represents the percentage of miRNAs from each cell types that contained at least one miRNA containing one of the motifs. These motifs could be found anywhere in the miRNA sequence. 
     The presence of these specific sequences was able to explain between 62-70% of the miRNA enrichment in the exosomes of the different cell lines. One of these sequences (GGAG) was previously reported to mediate exosome sorting in a cell type not studied here (human lymphoblasts, see Ritchie 2015), which suggests that these motifs might be evolutionarily conserved. 
     Interestingly, BAT ( FIG. 5A ), C2C12 ( FIG. 5B ) and 3T3-L1 ( FIG. 5C ) show a very similar pattern in the abundance of these exosomal sorting motifs, predominantly using UGUG; CAUG; or CUGG. In contrast, AML12 ( FIG. 5D ) and SVEC ( FIG. 5E ) predominantly use A/CGGG; CUGG; or GGAG exosomal sorting motifs. 
     Likewise, nucleotide motifs that might be associated with cellular enrichment and guide their retention were investigated. As shown in  FIG. 4B , five nucleotides sequences in the mature miRNA were significantly more abundant in those miRNAs that were retained in the cell. In this case, these five motifs were able to explain 34-56% of the miRNAs significantly enriched in the cells. As shown in  FIG. 5 , there is a clear hierarchy in the abundance of these cellular enrichment motifs, being CAGU&gt;ACAG&gt;AUUG&gt;UAGC&gt;CCCG in almost all the cases. 
     Thus, these data describe sorting motifs for enrichment of miRNAs in exosomal and cellular fractions. Some of these miRNA motifs were unique to particular types of cells, while other motifs were found across a range of cell types. 
     Example 6. Introduction or Removal of Motifs 
     In order to analyze whether the discovered motifs play a role in exosome sorting, experiments were performed to introduce or remove some of these motifs. Wild-type sequences for pre-miR-34c and pre-miR-693 and their flanking genomic 100 base pairs upstream and downstream were obtained from Ensembl database, flanked by restriction enzyme sites and ordered through Integrated DNA Technologies. For the mutations of the sequences in order to introduce or remove exosomal motifs, indicated nucleotides were changed in the guide strand sequence as well as complementary nucleotides in the passenger strand to maintain the same pre-miRNA structure, as predicted by RNAfold Web Server (University of Wien). These sequences were equally flanked by genomic 100 bp upstream and downstream and restriction enzymes. For both wild-type and mutated version, the sequences were cloned into the backbone lentivirus vector upon removal of the scramble miRNA cassette (MMIR000, System Biosciences). Plasmids were used to transfect BAT pre-adipocytes and positively incorporated cells were selected 6 days later by Flow Cytometry (MoFlo Cell Sorter, Beckman Coulter) for GFP signal. 
     Exosome isolation was performed again by ultracentrifugation method. RNA was isolated from the exosomes and cell bodies by TRIzol method. In order to measure the presence of the wild-type or mutated versions of miR-34c-5p and miR-693-3p, RNA was retrotranscribed by miRCURY LNA RT Kit (Qiagen 339320) following manufacturer&#39;s instructions. Specific LNA primers (Qiagen) were used in quantitative real-time PCR (qPCR) to distinguish wild-type and mutated versions of these two miRNAs. Expression for each miRNA was normalized respect to miR-138-5p, which has expression essentially identical between exosomes and cells. 
     miR-34c-5p (SEQ ID NO: 648) is a miRNA that was significantly enriched in the cell bodies of all cell types except hepatocytes (Table 1). The motifs UGUG or CAUG were introduced towards the 3′ end of the miR-34c-5p sequence with minimal changes in the miRNA sequence ( FIG. 6A ) in order to maintain the normal pre-miRNA structure ( FIG. 6B ), which is essential to display a regular processing by Dicer and potential recognition by RNA-binding proteins (RBPs) (see Bartel D P.  Cell  173(1):20-51 (2018) and Dominguez D et al.,  Mol Cell  70(5):854-867.e9 (2018)). Expectedly, when the wild-type version of miR-34c-5p was introduced, there was a higher presence in the cell body compared to the exosome fraction. However, when the mutant versions were introduced there was a shift in the mutated miR-34c-5p distribution, with expression being much more abundant in the exosomal fraction for both motifs and leading to a nearly statistically significant 4-fold enhancement of exosomal enrichment by UGUG introduction (SEQ ID NO: 701) and a significant 10-fold increase by CAUG introduction (SEQ ID NO: 702) ( FIG. 6C ). 
     Additionally, a novel 6-mer motif CGGGAG combining two shorter identified motifs, CGGG &amp; GGAG, was introduced in a CGGGAG mutant (SEQ ID NO: 703). The novel motif displays a 24- to 80-fold enrichment in exosome-enriched miRNAs from endothelial cells and hepatocytes. Due to this huge enrichment, the CGGGAG was termed a SuperEXOmotif. In this case, exosomal abundance was increased to a larger extent, leading to a final enrichment of 20-fold in abundance in exosomes versus cell bodies, which is much higher than the other motifs ( FIG. 6C ). Very interestingly, the introductions of the EXOmotif CAUG and SuperEXOmotif CGGGAG implied a complete shift in miRNA distribution from a very cellular-prone miRNA to a highly exosomal enriched miRNA ( FIG. 6C ). These data clearly suggest that these motifs play a role in miRNA sorting to exosomes. 
     In addition, the impact of removal of the identified exosome motif UGUG on exosome sorting was assessed. Wild-type miR-693-3p (SEQ ID NO: 6) is normally enriched in the exosomal fraction of all cell types. A mutated version of miR-693-3p lacking a UGUG motif (SEQ ID NO: 704) was studied. Again, these minor changes in the sequence ( FIG. 6D ) did not alter the expected secondary structure of this miRNA ( FIG. 6E ). When the wild-type version was overexpressed, miR-693-3p was found enriched in the exosome fraction. However, when the mutated version of miR-693-3p lacking a UGUG motif showed partially impaired sorting ( FIG. 6F ), again suggesting that this motif could be important for exporting miRNA into exosomes. 
     Example 7. Embodiments 
     The following numbered items provide embodiments as described herein, though the embodiments recited here are not limiting. 
     Item 1. A method for producing exosomes or exosome-like vesicles comprising miRNA in vitro comprising: 
     modifying a miRNA to include at least one exosomal sorting motif and/or removing any cellular retention motifs;
 
introducing the modified miRNA into a cell capable of producing an exosome or exosome-like vesicle under conditions that will result in expression of the modified miRNA; and
 
optionally, collecting the produced exosomes or exosome-like vesicles, wherein the exosomal sorting motif is UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, or CGGGAG, and the cell retention motif, if present, is CAGU, ACAG, AUUG, UAGC, or CCCG.
 
     Item 2. A method of treating a subject in need of gene silencing comprising administering to the subject an exosome, wherein the exosome is produced in vitro by a) modifying a miRNA to include at least one exosomal sorting motif and/or removing any cellular retention motifs, and b) introducing the modified miRNA into an exosome- or exosome-like vesicle producing cell under conditions that will result in expression of the modified miRNA, and collecting the produced exosome comprising the modified miRNA, wherein the exosomal sorting motifs is selected from UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, and CGGGAG and the cellular retention motif, if present, is selected from CAGU, ACAG, AUUG, UAGC, and CCCG. 
     Item 3. The method of item 1 or 2, wherein the miRNA comprises one exosomal sorting motif. 
     Item 4. The method of item 1 or 2, wherein the miRNA comprises more than one exosomal sorting motif. 
     Item 5. The method of item 1, further comprising administering the exosome or exosome-like vesicle to a subject. 
     Item 6. The method of item 1 or 2, wherein modifying the miRNA with an exosomal sorting motif results in more miRNA in the exosome as compared to an exosome produced with a miRNA not modified with an exosomal sorting motif. 
     Item 7. The method of item 1 or 2, wherein the removal of the cellular retention motif results in more miRNA in the exosome as compared to an exosome produced with a miRNA comprising a cellular retention motif. 
     Item 8. The method of item 1 or 2, wherein the miRNA contains a cell retention motif and wherein the cell retention motif is removed. 
     Item 9. A method for retaining miRNA inside a cell in vitro comprising: 
     modifying a miRNA to include at least one cell retention motif and/or removing any exosomal sorting motifs; and
 
introducing the modified miRNA into a cell capable of producing an exosome or exosome-like vesicle under conditions that will result in expression of the modified miRNA, wherein the cell retention motif is CAGU, ACAG, AUUG, UAGC, or CCCG, and the exosomal sorting motif, if present is UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, or CGGGAG.
 
     Item 10. A method for treating a subject in need of gene silencing comprising: 
     collecting the subject&#39;s cells and manipulating them ex vivo to express a miRNA having at least one cellular retention motif and/or removing any exosomal sorting motifs, and administering the ex vivo manipulated cell comprising the modified miRNA to the same or different subject from which it was collected, wherein the cellular retention motif is selected from CAGU, ACAG, AUUG, UAGC, and CCCG, and the exosomal sorting motif, if present, is selected from UGUG, GGAG, CAUG, GGCA/G, A/CGGG, CUGG, and CGGGAG. 
     Item 11. The method of item 9 or 10, wherein the miRNA comprises one cellular retention motif. 
     Item 12. The method of item 9 or 10, wherein the miRNA comprises more than one cellular retention motif. 
     Item 13. The method of item 9 or 10, wherein the addition of the cellular retention motif reduces the export of the miRNA into an exosome or exosomal-like vesicle. 
     Item 14. The method of item 9 or 10, wherein the removal of the exosomal sorting motif reduces the export of the miRNA into an exosome or exosomal-like vesicle. 
     Item 15. The method of item 9, further comprising administering the cell to a subject. 
     Item 16. The method of item 10 or 15, wherein the miRNA levels in non-implanted cell-types after administration to the subject are reduced as compared to levels in subject administered a non-modified miRNA containing cell. 
     Item 17. The method of any one of the preceding items, wherein the cell is an adipocyte, muscle cell, hepatocyte, or vascular endothelial cell. 
     Item 18. The method of item 17, wherein the adipocyte is a white adipocyte or brown adipocyte. 
     Item 19. The method of item 18, wherein the white adipocyte is a 3T3-L1 cell. 
     Item 20. The method of item 18, wherein the brown adipocyte is a BAT cell. 
     Item 21. The method of item 17, wherein the muscle cell is a C2C12 cell. 
     Item 22. The method of item 17, wherein the hepatocyte is an AML12 cell. 
     Item 23. The method of item 17, wherein the vascular endothelial cell is a SVEC cell. 
     Item 24. The method of item 1 or 2, wherein the cell is a hepatocyte or endothelial cell and the exosomal sorting motif is A/CGGG; CUGG; GGAG; or CGGGAG. 
     Item 25. The method of item 1 or 2, wherein the cell is a brown or white adipocyte or muscle cell and the exosomal sorting motif is UGUG; CAUG; CUGG; or CGGGAG. 
     Item 26. The method of any one of the preceding items, wherein the miRNA is any one of the miRNAs of SEQ ID Nos: 1-704. 
     EQUIVALENTS 
     The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof. 
     As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., +/−5-10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.