長鏈非編碼核糖核酸

長鏈非編碼核糖核酸。長鏈非編碼核糖核酸的丰度.近年研究顯示人類基因組中的轉錄只有五分之一與蛋白編碼基因有關。儘管如此，在這些cDNA文庫中明確鑑定非編碼RNA類仍是充滿挑戰的，因為該方法無法區分非編碼轉錄物及蛋白編碼轉錄物。長鏈非編碼核糖核酸的基因組組織.目前將哺乳動物基因組的全景描繪為：長段的基因間空間將多個轉錄“焦點”分割開。儘管編碼RNA及非編碼RNA的交錯排列具備一定的丰度和保守性，並可能意味著它們兩者之間具有某些生物學關聯性，但仍無法對這些複雜的焦點結構進行簡單的評價。GENCODE共同體已綜合性整理及分析了一些人類長鏈非編碼RNA的註釋及它們的基因組結構、修飾、細胞定位及組織表達譜。長鏈非編碼核糖核酸的保守性.如微核糖核酸及小核仁核糖核酸等的眾多小型核糖核酸都顯現出了跨多物種的保守性。非編碼核糖核酸的保守性差可能是近期且快速的適應性選擇的結果。例如，非編碼核糖核酸較蛋白編碼基因可能對進化壓力可塑性更強，如"Xist"或"Air"等的許多世系特異性非編碼RNA的存在可以證明這一點，這支援了上述論點。長鏈非編碼核糖核酸的功能.cDNA文庫的大規模測序及更先進的基於下一代測序的轉錄組測序表明哺乳動物中長鏈非編碼核糖核酸的數量大約是幾萬條。然而，雖然越來越多的證據提示大多數長鏈非編碼核糖核酸具有功能。長鏈非編碼RNA類在基因轉錄調控中的作用.長鏈非編碼RNA類在基因特異性轉錄中的作用.RNA轉錄在真核生物中是一個受到嚴密調控的過程。非編碼RNA可以靶向該程序的多個方面，包括靶向轉錄啟用因子或轉錄抑制因子、如RNA聚合酶。非編碼RNA將這些機制結合在一起可以組成為一個包括轉錄因子在內的調控網路，可以精細地調控複雜真核生物的基因表達。非編碼RNA透過多種不同的機制調節轉錄因子的功能，包括充當共調控因子的角色、修飾轉錄因子的活性或是調控共調控因子的活性。例如，非編碼RNA Evf-2作為同源異形框轉錄因子Dlx2的共啟用因子，Dlx2在前腦發育及神經發生中起到重要作用。區域性的非編碼RNA類可以招募轉錄機制對附近蛋白編碼基因的轉錄加以調控。TLS並在轉錄程式控制中整合它們的功能。在X染色體失活的情況下一些基因仍可以轉錄，近期對逃避染色體失活控制的染色體區域進行研究，發現其中表達的長鏈非編碼RNA可能介導了這一過程。長鏈非編碼RNA調控基礎轉錄機器.非編碼RNA還可以靶向通用轉錄因子，後者是RNAPⅡ轉錄所有基因所必需的，當細胞處於應激狀況下可以抑制全域性延伸。這些例子中的機制可以繞開單個啟動子上特異性的調控模式，介導起始及延伸轉錄機器工作水平發生直接改變，提供了迅速影響基因表達全域性改變的方法。現也證明非編碼重複序列有著介導全域性調控的能力。人類的短散在核內。對Alu元件的RNA轉錄物中的功能序列進行分析後，發現其亦有類似於蛋白質轉錄因子中結構域的模組化結構。 These two loosely-structured domains may even be concatenated to other ncRNAs such as B1 elements to impart their repressive role (Mariner &amp; Walters 2008). The abundance and distribution of Alu elements and similar repetitive elements throughout the mammalian genome may be partly due to these functional domains being co-opted into other long ncRNAs during evolution, with the presence of functional repeat sequence domains being a common characteristic of several known long ncRNAs including Kcnq1ot1, Xlsirt and Xist (Mattick 2003; Mohammad 2008; Wutz 2002; Zearfoss 2003).除了熱休克外，如病毒感染、, the expression of SINE elements (including Alu, B1, and B2 RNAs) increases during cellular stress such as viral infection (Singh 1985) in some cancer cells (Tang 2005) where they may similarly regulate global changes to gene expression. The ability of Alu and B2 RNA to bind directly to RNAP II provides a broad mechanism to repress transcription (Espinoza 2004; Mariner &amp; Walters 2008). Nevertheless, there are specific exceptions to this global response where Alu or B2 RNAs are not found at activated promoters of genes undergoing induction, such as the heat shock genes (Mariner &amp; Walters 2008). This additional hierarchy of regulation that exempts individual genes from the generalised repression also involves a long ncRNA, heat shock RNA-1 (HSR-1). It was argued that HSR-1 is present in all cells in an inactive state, but upon stress is activated to induce the expression of heat shock genes (Shamovsky 2006). The authors found that this activation involves a conformational alteration to the structure of HSR-1 in response to rising temperatures, thereby permitting its interaction with the transcriptional activator HSF-1 that subsequently undergoes trimerisation and induces the expression of heat shock genes (Shamovsky 2006). In the broad sense, these examples illustrate a regulatory circuit nested witin ncRNAs whereby Alu or B2 RNAs repress general gene expression, while other ncRNAs activate the expression of specific genes.長鏈非編碼RNA類在基因轉錄後調控中的作用.除了在轉錄水平上調控，ncRNAs 也在轉錄後水平調控mRNA加工的不同方面。與小調控RNAs，例如微小RNAs和小核仁RNAs，類似，ncRNAs 的功能包括與目標mRNA進行互補鹼基配對。互補ncRNA和mRNA形成的RNA雙鏈可能為需要結合反式作用因子的mRNA募集關鍵因子，可能影響轉錄後水平基因表達的每一步，包括前體mRNA加工，剪接，運輸，翻譯以及降解。長鏈非編碼RNA類在剪接調控中的作用.The splicing of mRNA can induce its translation and functionally diversify the repertoire of proteins it encodes. The Zeb2 mRNA, which has a particularly long 5’UTR, requires the retention of a 5’UTR intron that contains an internal ribosome entry site for efficient translation (Beltran 2008). However, retention of the intron is dependent on the expression of an antisense transcript that complements the intronic 5’ splice site (Beltran 2008). Therefore, the ectopic expression of the antisense transcript represses splicing and induces translation of the Zeb2 mRNA during mesenchymal development. Likewise, the expression of an overlapping antisense Rev-ErbAα2 transcript controls the alternative splicing of the thyroid hormone receptor ErbAα2 mRNA to form two antagonistic isoforms (Munroe 1991).長鏈非編碼RNA類在翻譯調控中的作用.NcRNA may also apply additional regulatory pressures during translation, a property particularly exploited in neurons where the dendritic or axonal translation of mRNA in response to synaptic activity contributes to changes in synaptic plasticity and the remodelling of neuronal networks. The RNAP III transcribed BC1 and BC200 ncRNAs, that previously derived from tRNAs, are expressed in the mouse and human central nervous system, respectively (Tiedge 1993; Tiedge 1991). BC1 expression is induced in response to synaptic activity and synaptogenesis and is specifically targeted to dendrites in neurons (Muslimov 1998). Sequence complementarity between BC1 and regions of various neuron-specific mRNAs also suggest a role for BC1 in targeted translational repression (Wang 2005). Indeed it was recently shown that BC1 is associated with translational repression in dendrites to control the efficiency of dopamine D2 receptor-mediated transmission in the striatum (Centonze 2007) and BC1 RNA-deleted mice exhibit behavioural changes with reduced exploration and increased anxiety (Lewejohann 2004).長鏈非編碼RNA類在siRNA導向的基因調控中的作用.In addition to masking key elements within single-stranded RNA, the formation of double-stranded RNA duplexes can also provide a substrate for the generation of endogenous siRNAs (endo-siRNAs) in Drosophila and mouse oocytes (Golden 2008). The annealing of complementary sequences, such as antisense or repetitive regions between transcripts, forms an RNA duplex that may be processed by Dicer-2 into endo-siRNAs. Also, long ncRNAs that form extended intramolecular hairpins may be processed into siRNAs, compellingly illustrated by the esi-1 and esi-2 transcripts (Czech 2008). Endo-siRNAs generated from these transcripts seem particularly useful in suppressing the spread of mobile transposon elements within the genome in the germline. However, the generation of endo-siRNAs from antisense transcripts or pseudogenes may also silence the expression of their functional counterparts via RISC effector complexes, acting as an important node that integrates various modes of long and short RNA regulation, as exemplified by the Xist and Tsix (see above) (Ogawa 2008).長鏈非編碼RNA類在表觀遺傳調控中的作用.包括組蛋白和DNA甲基化、組蛋白乙醯化和SUMO化等在內的表觀遺傳修飾影響了染色體生物學的眾多方面，主要包括透過對廣大染色質區域進行重塑從而調控大量基因。果蠅屬中的長鏈非編碼RNA類透過將三胸蛋白Ash1募集到同源異形調控元件並指導其發揮染色質修飾作用的方式誘導同源異形基因"Ubx"的表達。因此，相關的反義非編碼RNA類表達發生異常可能繼而沉默了抑癌基因，從而走向癌症發生。基因印記.最近非編碼RNA指導的染色質修飾主題最初是從基因組印記的現象中引出的，基因組印記是僅從母系或父系染色體兩者中的一個表達出等位基因的現象。一般來說，印記基因是呈簇狀排列於染色體上，這提示：印記的機制是作用於區域性的染色質區域上而不是針對單個基因。這些基因簇常常與長鏈非編碼RNA相關：長鏈非編碼RNA的表達量與在相同等位上相連鎖的蛋白編碼基因受到抑制的程度呈正相關。幾乎所有位於"Kcnq1"基因座Almost all the genes at the Kcnq1 loci are maternally inherited, except the paternally expressed antisense ncRNA Kcnqot1 (Mitsuya 1999). Transgenic mice with truncated Kcnq1ot fail to silence the adjacent genes, suggesting that Kcnqot1 is crucial to the imprinting of genes on the paternal chromosome (Mancini-Dinardo 2006). It appears that Kcnqot1 is able to direct the trimethylation of lysine 9 (H3K9me3) and 27 of histone 3 (H3K27me3) to an imprinting centre that overlaps the Kcnqot1 promoter and actually resides within a Kcnq1 sense exon (Umlauf 2004). Similar to HOTAIR (see above), Eed-Ezh2 Polycomb complexes are recruited to the Kcnq1 loci paternal chromosome, possibly by Kcnqot1, where they may mediate gene silencing through repressive histone methylation (Umlauf 2004). A differentially methylated imprinting centre also overlaps the promoter of a long antisense ncRNA Air that is responsible for the silencing of neighbouring genes at the Igf2r locus on the paternal chromosome (Sleutels 2002; Zwart 2001). The presence of allele-specific histone methylation at the Igf2r locus suggests Air also mediates silencing via chromatin modification (Fournier 2002)."Xist"與X-染色體失活.The inactivation of a X-chromosome in female placental mammals is directed by one of the earliest and best characterized long ncRNAs, Xist (Wutz 2007). The expression of Xist from the future inactive X-chromosome, and its subsequent coating of the inactive X-chromosome, occurs during early embryonic stem cell differentiation. Xist expression is followed by irreversible layers of chromatin modifications that include the loss of the histone (H3K9) acetylation and H3K4 methylation that are associated with active chromatin, and the induction of repressive chromatin modifications including H4 hypoacetylation, H3K27 trimethylation (Wutz 2007), H3K9 hypermethylation and H4K20 monomethylation as well as H2AK119 monoubiquitylation. These modifications coincide with the transcriptional silencing of the X-linked genes (Morey 2004). Xist RNA also localises the histone variant macroH2A to the inactive X–chromosome (Costanzi 1998). There are additional ncRNAs that are also present at the Xist loci, including an antisense transcript Tsix, which is expressed from the future active chromosome and able to repress Xist expression by the generation of endogenous siRNA (Ogawa 2008). Together these ncRNAs ensure that only one X-chromosome is active in female mammals.端粒非編碼RNA類.Telomeres form the terminal region of mammalian chromosomes and are essential for stability and aging and play central roles in diseases such as cancer (Blasco 2007). Telomeres have been long considered transcriptionally inert DNA-protein complexes until it was recently shown that telomeric repeats may be transcribed as telomeric RNAs (TelRNAs) (Schoeftner 2008) or telomeric repeat-containing RNAs (Azzalin 2007). These ncRNAs are heterogeneous in length, transcribed from several sub-telomeric loci and physically localise to telomeres. Their association with chromatin, which suggests an involvement in regulating telomere specific heterochromatin modifications, is repressed by SMG proteins that protect chromosome ends from telomere loss (Azzalin 2007). In addition, TelRNAs block telomerase activity in vitro and may therefore regulate telomerase activity (Schoeftner 2008). Although early, these studies suggest an involvement for telomeric ncRNAs in various aspects of telomere biology.