長(zhǎng)鏈非編碼RNA

跳轉(zhuǎn)到： 導(dǎo)航, 搜索
A+醫(yī)學(xué)百科 >> 長(zhǎng)鏈非編碼RNA

長(zhǎng)鏈非編碼RNA類（英語(yǔ)：Long non-coding RNAs，簡(jiǎn)稱為lncRNA）指的是長(zhǎng)于200核苷酸的不編碼蛋白質(zhì)的轉(zhuǎn)錄物（Perkel 2013）。該有些武斷的界定將長(zhǎng)鏈非編碼RNA類與較小的調(diào)控RNA類區(qū)分開(kāi)來(lái)，后者如微RNA類（miRNAs）、小干擾RNA類（siRNAs）、Piwi互作RNA類（piRNAs）、小核仁RNA類（snoRNAs）及其它短RNA類（Ma 2013）。

目錄

長(zhǎng)鏈非編碼RNA類的豐度

近年研究顯示人類基因組中的轉(zhuǎn)錄只有五分之一與蛋白編碼基因有關(guān)（Kapranov 2007），這說(shuō)明至少有較編碼RNA序列四倍多的長(zhǎng)鏈非編碼RNA。而像FANTOM（哺乳動(dòng)物cDNA功能注釋）等的大規(guī)模互補(bǔ)DNA（cDNA）測(cè)序計(jì)劃揭示了轉(zhuǎn)錄的復(fù)雜性（Carninci 2005）。FANTOM3計(jì)劃從約一萬(wàn)個(gè)不同的基因座中鑒定出了約三萬(wàn)五千條非編碼轉(zhuǎn)錄物它們有著與mRNA類類似的特征，包括5'端有帽、受到剪接及多聚腺苷酸化，但只有很小的開(kāi)放閱讀框（ORF）或根本沒(méi)有（Carninci 2005）。然而長(zhǎng)鏈非編碼RNA的豐度是意料之外的，其數(shù)目代表的是保守估計(jì)的最低值，因?yàn)檫@種方法忽略了許多單獨(dú)的轉(zhuǎn)錄物及非多腺苷酸化的轉(zhuǎn)錄物（瓦片陣列數(shù)據(jù)顯示出40%以上的轉(zhuǎn)錄物是非多腺苷酸化的）（Cheng 2005）。盡管如此，在這些cDNA文庫(kù)中明確鑒定非編碼RNA類仍是充滿挑戰(zhàn)的，因?yàn)樵摲椒o(wú)法區(qū)分非編碼轉(zhuǎn)錄物及蛋白編碼轉(zhuǎn)錄物。

長(zhǎng)鏈非編碼RNA類的基因組組織

目前將哺乳動(dòng)物基因組的全景描繪為：長(zhǎng)段的基因間空間將多個(gè)轉(zhuǎn)錄“焦點(diǎn)”分割開(kāi)（Carninci 2005）。然而長(zhǎng)鏈非編碼RNA類正位于這些基因間區(qū)段中并由此轉(zhuǎn)錄出來(lái)，其中大多數(shù)是與其它轉(zhuǎn)錄物之間呈錯(cuò)綜復(fù)雜的正義或反義重疊，這些轉(zhuǎn)錄物往往包括了蛋白編碼基因（Kapranov 2007）。在正義或反義鏈上的多個(gè)不同的編碼或非編碼轉(zhuǎn)錄物共享這些轉(zhuǎn)錄焦點(diǎn)中的基因組序列（Birney 2007），使得這些重疊的亞型之間產(chǎn)生復(fù)雜的層次結(jié)構(gòu)。例如，8961個(gè)cDNA中的3012個(gè)曾被FANTOM2計(jì)劃注釋為編碼序列中的一段截短序列，但后來(lái)又重新被指定為蛋白編碼cDNA中的新非編碼RNA變異體（Carninci 2005）。盡管編碼RNA及非編碼RNA的交錯(cuò)排列具備一定的豐度和保守性，并可能意味著它們兩者之間具有某些生物學(xué)關(guān)聯(lián)性，但仍無(wú)法對(duì)這些復(fù)雜的焦點(diǎn)結(jié)構(gòu)進(jìn)行簡(jiǎn)單的評(píng)價(jià)。

GENCODE共同體已綜合性整理及分析了一些人類長(zhǎng)鏈非編碼RNA的注釋及它們的基因組結(jié)構(gòu)、修飾、細(xì)胞定位及組織表達(dá)譜（Derrien 2012）。他們的分析結(jié)果說(shuō)明人類長(zhǎng)鏈非編碼RNA易形成具有兩個(gè)外顯子的轉(zhuǎn)錄物（Derrien 2012）。

受轉(zhuǎn)錄因子調(diào)控的長(zhǎng)鏈非編碼RNA類

如lncRNA芯片及RNA-Seq等高通量基因組技術(shù)往往會(huì)產(chǎn)生一系列令人感興趣的長(zhǎng)鏈非編碼RNA，但對(duì)于這些長(zhǎng)鏈非編碼RNA基因所受的轉(zhuǎn)錄調(diào)控卻知之甚少。根據(jù)來(lái)自ENCODE計(jì)劃的轉(zhuǎn)錄因子（TFs）ChIP-Seq峰值列表和來(lái)自GENCODE的已注釋人類長(zhǎng)鏈非編碼RNA，哈爾濱工業(yè)大學(xué)的研究團(tuán)隊(duì)開(kāi)發(fā)了一個(gè)基于網(wǎng)絡(luò)界面的軟件——TF2lncRNA， High-throughput genomic technologies like lncRNA microarray and RNA-Seq often generate a set of lncRNAs of interest, yet little is known about the transcriptional regulation of the set of lncRNA genes. Here, based on ChIP-Seq peak lists of transcription factors (TFs) from ENCODE and annotated human lncRNAs from GENCODE, we developed a web-based interface titled ‘TF2lncRNA’, where TF peaks from each ChIP-Seq experiment are crossed with the genomic coordinates of a set of input lncRNAs, to identify which TFs present a statistically significant number of binding sites (peaks) within the regulatory region of the input lncRNA genes. The input can be a set of co-expressed lncRNA genes, or any other cluster of lncRNA genes. Users can thus infer which TFs are likely to be common transcription regulators of the set of lncRNAs. In addition, users can retrieve all lncRNAs potentially regulated by a specific TF in a specific cell line of interest, or retrieve all TFs that have one or more binding sites in the regulatory region of a given lncRNA in the specific cell line. TF2LncRNA is an efficient and easy-to-use web-based tool accessible at http://mlg.hit.edu.cn/tf2lncrna.

長(zhǎng)鏈非編碼RNA類的保守性

如微RNA類及小核仁RNA類等的眾多小型RNA類都顯現(xiàn)出了跨多物種的保守性（Bentwich 2005）。與之相反，大多數(shù)長(zhǎng)鏈非編碼RNA則保守性不強(qiáng)，這一點(diǎn)常被引用為其不具備功能的證據(jù)（Brosius 2005；Struhl 2007）。然而，如Air及Xist等經(jīng)過(guò)詳細(xì)研究的長(zhǎng)鏈非編碼RNA，它們的保守性也很差（Nesterova 2001），這意味著非編碼RNA類可能受到不同的選擇壓力（Pang 2006）。mRNA必須保守密碼子的正常用法并防止單個(gè)長(zhǎng)ORF中出現(xiàn)移碼突變，然而對(duì)長(zhǎng)鏈非編碼RNA的選擇壓力可能只會(huì)令其保守其中的較短區(qū)域，這些較短區(qū)域?qū)τ诮Y(jié)構(gòu)或序列特異性相互作用較為關(guān)鍵。因此，我們可見(jiàn)選擇壓力只會(huì)作用于長(zhǎng)鏈非編碼RNA轉(zhuǎn)錄物的小塊區(qū)域。仍然要看到：盡管長(zhǎng)鏈非編碼RNA總體來(lái)說(shuō)保守性較低，但仍可見(jiàn)許多長(zhǎng)鏈非編碼RNA具有較強(qiáng)的保守元件。例如，高度保守的phastCons元件中有19%存在于已知的內(nèi)含子中，而其它32%存在于未注釋的區(qū)域之中（Siepel 2005）。此外，人類長(zhǎng)鏈非編碼RNA中的具有代表性的一類長(zhǎng)鏈非編碼RNA在堿基取代和插入/缺失速率方面顯現(xiàn)出較小但顯著的降低，這一現(xiàn)象指示了凈化選擇壓力使得轉(zhuǎn)錄物的完整性得到保守，這在序列、啟動(dòng)子及剪接三種水平上體現(xiàn)出來(lái)（Ponjavic 2007）。

非編碼RNA的保守性差可能是近期且快速的適應(yīng)性選擇的結(jié)果。例如，非編碼RNA類較蛋白編碼基因可能對(duì)進(jìn)化壓力可塑性更強(qiáng)，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(diǎn)（Pang 2006）。相對(duì)于黑猩猩基因組來(lái)說(shuō)人類基因組中經(jīng)受近期進(jìn)化改變的保守區(qū)域確實(shí)主要存在于非編碼區(qū)域，其中很多已有詳盡描述（Pollard 2006；Pollard 2006）。其中包括一條名為HAR1F的非編碼RNA，該基因在人類中經(jīng)歷了快速的進(jìn)化變化，且特異性地在人類新皮質(zhì)的卡哈爾-雷濟(jì)厄斯氏細(xì)胞中特異性表達(dá)（Pollard 2006）。現(xiàn)有報(bào)道稱許多功能已確定的RNA進(jìn)化速率也很快（Pang 2006；Smith 2004），這可能由于這些序列受到結(jié)構(gòu)-功能約束時(shí)表現(xiàn)得更靈活，我們可以期待在這些序列中發(fā)現(xiàn)新的進(jìn)化方式。人類基因組中有數(shù)千條序列的一級(jí)序列保守性較差，但有證據(jù)顯示它們RNA二級(jí)結(jié)構(gòu)卻存在著保守性（Torarinsson 2006；Torarinsson 2008），這支持了上述論點(diǎn)。

長(zhǎng)鏈非編碼RNA類的功能

cDNA文庫(kù)的大規(guī)模測(cè)序及更先進(jìn)的基于下一代測(cè)序的轉(zhuǎn)錄組測(cè)序表明哺乳動(dòng)物中長(zhǎng)鏈非編碼RNA的數(shù)量大約是幾萬(wàn)條。然而，雖然越來(lái)越多的證據(jù)提示大多數(shù)長(zhǎng)鏈非編碼RNA具有功能（Mercer 2009；Dinger 2009），但相對(duì)只有一小部分已被證明有生物學(xué)重大意義。截至2012年十二月，約有127條長(zhǎng)鏈非編碼RNA在LncRNAdb（一個(gè)描述長(zhǎng)鏈非編碼RNA的文獻(xiàn)數(shù)據(jù)庫(kù)）中有功能注釋（Amral 2011）。

長(zhǎng)鏈非編碼RNA類在基因轉(zhuǎn)錄調(diào)控中的作用

長(zhǎng)鏈非編碼RNA類在基因特異性轉(zhuǎn)錄中的作用

RNA轉(zhuǎn)錄在真核生物中是一個(gè)受到嚴(yán)密調(diào)控的過(guò)程。非編碼RNA可以靶向該進(jìn)程的多個(gè)方面，包括靶向轉(zhuǎn)錄激活因子或轉(zhuǎn)錄抑制因子、如RNA聚合酶（RNAP）Ⅱ等轉(zhuǎn)錄反應(yīng)中的各組分、甚至是DNA雙螺旋結(jié)構(gòu)，以達(dá)到調(diào)控基因轉(zhuǎn)錄及表達(dá)的目的（Goodrich 2006）。非編碼RNA將這些機(jī)制結(jié)合在一起可以組成為一個(gè)包括轉(zhuǎn)錄因子在內(nèi)的調(diào)控網(wǎng)絡(luò)，可以精細(xì)地調(diào)控復(fù)雜真核生物的基因表達(dá)。

非編碼RNA通過(guò)多種不同的機(jī)制調(diào)節(jié)轉(zhuǎn)錄因子的功能，包括充當(dāng)共調(diào)控因子的角色、修飾轉(zhuǎn)錄因子的活性或是調(diào)控共調(diào)控因子的活性。例如，非編碼RNA Evf-2作為同源異形框轉(zhuǎn)錄因子Dlx2的共激活因子，Dlx2在前腦發(fā)育及神經(jīng)發(fā)生中起到重要作用（Feng 2006；Panganiban 2002）。Evf-2轉(zhuǎn)錄自位于DLX5|Dlx5與DLX6|Dlx6基因之間的超保守元件，音猬因子在前腦發(fā)育過(guò)程中誘導(dǎo)該長(zhǎng)鏈的轉(zhuǎn)錄（Feng 2006）。Evf-2接著將Dlx2轉(zhuǎn)錄因子招募到同一個(gè)超保守元件處，Dlx2在此處誘導(dǎo)Dlx5的表達(dá)。哺乳動(dòng)物基因組中存在其它一些可轉(zhuǎn)錄且執(zhí)行增強(qiáng)子功能的超級(jí)保守或高度保守元件，這提示Evf-2可作為范例闡述脊椎動(dòng)物生長(zhǎng)過(guò)程中以復(fù)雜表達(dá)的形式嚴(yán)密調(diào)控重要發(fā)育基因的普遍機(jī)制（Pennacchio 2006；Visel 2008）。近期研究也確實(shí)發(fā)現(xiàn)與之類似的其它非編碼超保守元件的轉(zhuǎn)錄及表達(dá)在人類白血病中出現(xiàn)異常，且促進(jìn)結(jié)腸癌細(xì)胞的凋亡，這提示了它們涉及到腫瘤形成（Calin 2007）。

局部的非編碼RNA類可以招募轉(zhuǎn)錄機(jī)制對(duì)附近蛋白編碼基因的轉(zhuǎn)錄加以調(diào)控。TLS（英語(yǔ)：translocated in liposarcoma）是一種結(jié)合RNA的蛋白，它結(jié)合到CREB結(jié)合蛋白和組蛋白乙酰基轉(zhuǎn)移酶p300上并抑制這兩者在靶基因周期蛋白D1上的活性，從而起到抑制后者的作用。作為DNA受損信號(hào)的響應(yīng)，長(zhǎng)鏈非編碼RNA以低水平表達(dá)出來(lái)并拴在周期蛋白D1基因的5'調(diào)控區(qū)域上，這指導(dǎo)了TLS招募到周期蛋白D1啟動(dòng)子上（Wang 2008）。除此之外，這些局部的非編碼RNA作為配體調(diào)控TLS的活性。從更廣泛的層面上說(shuō)，這一機(jī)制使得細(xì)胞可以利用RNA結(jié)合蛋白（它們組成了哺乳動(dòng)物蛋白質(zhì)組中的最龐大的種類之一）并在轉(zhuǎn)錄程序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(zhuǎn)錄，近期對(duì)逃避染色體失活控制的染色體區(qū)域進(jìn)行研究，發(fā)現(xiàn)其中表達(dá)的長(zhǎng)鏈非編碼RNA可能介導(dǎo)了這一過(guò)程（Reinius 2010）。

長(zhǎng)鏈非編碼RNA調(diào)控基礎(chǔ)轉(zhuǎn)錄機(jī)器

非編碼RNA還可以靶向通用轉(zhuǎn)錄因子，后者是RNAPⅡ轉(zhuǎn)錄所有基因所必需的（Goodrich 2006）。這些通用因子包括了起始復(fù)合體中組裝在啟動(dòng)子上或涉及轉(zhuǎn)錄延伸的部件。轉(zhuǎn)錄自二氫葉酸還原酶（DHFR）基因上游次要啟動(dòng)子的一條非編碼RNA進(jìn)入DHFR主要啟動(dòng)子，形成穩(wěn)定的RNA-DNA三股螺旋以阻止轉(zhuǎn)錄輔因子TFⅡB結(jié)合到其上（Martianov 2007）。已知真核染色體上存在著數(shù)千個(gè)三股螺旋（Lee 1987），這一調(diào)控基因表達(dá)的新機(jī)制可能事實(shí)上代表這些三股螺旋在控制啟動(dòng)子上起到的廣泛作用。U1非編碼RNA通過(guò)結(jié)合到TFⅡH上并刺激其對(duì)RNAPⅡ的C-端以實(shí)現(xiàn)誘導(dǎo)轉(zhuǎn)錄起始（Kwek 2002）。相反，非編碼RNA 7SK可通過(guò)下列方式起到抑制轉(zhuǎn)錄延伸的作用：7SK首先與HEXIM1/2結(jié)合，形成抑制性復(fù)合物，該復(fù)合物阻止PTEFb通用轉(zhuǎn)錄因子去磷酸化RNAPⅡ的C-端結(jié)構(gòu)域（Kwek 2002；Yang 2001；Yik 2003），當(dāng)細(xì)胞處于應(yīng)激狀況下可以抑制全局延伸。這些例子中的機(jī)制可以繞開(kāi)單個(gè)啟動(dòng)子上特異性的調(diào)控模式，介導(dǎo)起始及延伸轉(zhuǎn)錄機(jī)器工作水平發(fā)生直接改變，提供了迅速影響基因表達(dá)全局改變的方法。

現(xiàn)也證明非編碼重復(fù)序列有著介導(dǎo)全局調(diào)控的能力。人類的短散在核內(nèi)（SINE）Alu元件及小鼠中同源的B1和B2元件是基因組中豐度最高的可移動(dòng)性元件，分別組成了人類和小鼠基因組的約10%和約6%（Lander 2001；Waterston 2002）。在如熱休克等環(huán)境應(yīng)激情況下這些元件被RNAPⅢ轉(zhuǎn)錄為非編碼RNA（Liu 1995），后者接下來(lái)會(huì)以高親和度的方式與RNAPⅡ結(jié)合并阻止其形成為有活性的前起始復(fù)合物（Allen 2004；Espinoza 2004；Espinoza 2007；Mariner & Walters 2008）。這使得在響應(yīng)應(yīng)激的情況下可以大范圍并迅速抑制基因的表達(dá)（Allen 2004；Mariner & Walters 2008）。

對(duì)Alu元件的RNA轉(zhuǎn)錄物中的功能序列進(jìn)行分析后，發(fā)現(xiàn)其亦有類似于蛋白質(zhì)轉(zhuǎn)錄因子中結(jié)構(gòu)域的模塊化結(jié)構(gòu)（Shamovsky 2008）。Alu元件RNA包括兩個(gè)“臂”，每個(gè)臂都可以結(jié)合到一個(gè)RNAPⅡ分子上；體外實(shí)驗(yàn)表明該RNA還具有兩個(gè)調(diào)控結(jié)構(gòu)域，起到抑制RNAPⅡ轉(zhuǎn)錄活性的作用（Mariner 2008）。 These two loosely-structured domains may even be concatenated to other ncRNAs such as B1 elements to impart their repressive role (Mariner & 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 & 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 & 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(zhǎng)鏈非編碼RNA類在基因轉(zhuǎn)錄后調(diào)控中的作用

In addition to regulating transcription, ncRNAs also control various aspects of post-transcriptional mRNA processing. Similar to small regulatory RNAs such as microRNAs and snoRNAs, these functions often involve complementary base pairing with the target mRNA. The formation of RNA duplexes between complementary ncRNA and mRNA may mask key elements within the mRNA required to bind trans-acting factors, potentially effecting any step in post-transcriptional gene expression including pre-mRNA processing and splicing, transport, translation, and degradation.

長(zhǎng)鏈非編碼RNA類在剪接調(diào)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(zhǎng)鏈非編碼RNA類在翻譯調(diào)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(zhǎng)鏈非編碼RNA類在siRNA導(dǎo)向的基因調(diào)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(zhǎng)鏈非編碼RNA類在表觀遺傳調(diào)控中的作用

包括組蛋白和DNA甲基化、組蛋白乙酰化和SUMO化等在內(nèi)的表觀遺傳修飾影響了染色體生物學(xué)的眾多方面，主要包括通過(guò)對(duì)廣大染色質(zhì)區(qū)域進(jìn)行重塑從而調(diào)控大量基因（Kiefer 2007；Mikkelsen 2007）。一段時(shí)間以來(lái)，RNA作為染色質(zhì)的有機(jī)組成部分已被人知曉（Nickerson 1989；Rodriguez-Campos 2007），但現(xiàn)在我們才開(kāi)始認(rèn)識(shí)到RNA在涉及到染色質(zhì)修飾通路上的意義（Chen 2008；Rinn 2007；Sanchez-Elsner 2006）。

果蠅屬中的長(zhǎng)鏈非編碼RNA類通過(guò)將三胸蛋白Ash1募集到同源異形調(diào)控元件并指導(dǎo)其發(fā)揮染色質(zhì)修飾作用的方式誘導(dǎo)同源異形基因Ubx的表達(dá)（Sanchez-Elsner 2006）。后來(lái)發(fā)現(xiàn)哺乳動(dòng)物中也存在著相似的調(diào)控模式：認(rèn)為強(qiáng)大的表觀遺傳機(jī)制奠定了胚胎同源異形基因家族的表達(dá)譜，而同源異形基因家族是貫穿整個(gè)人體發(fā)育過(guò)程中持續(xù)發(fā)揮作用的重要因子（Mazo 2007；Rinn 2007）。人類同源異形基因家族確實(shí)與數(shù)百個(gè)非編碼RNA之間有著相關(guān)性，這些非編碼RNA在人體發(fā)育的時(shí)空軸上按順序表達(dá)，這些非編碼RNA也定義染色質(zhì)各區(qū)域中組蛋白甲基化程度的差異以及RNA聚合酶可進(jìn)入染色質(zhì)的程度（Rinn 2007）。其中一條名為HOTAIR的轉(zhuǎn)錄自HOXC基因座的非編碼RNA通過(guò)改變組蛋白三甲基化狀態(tài)從而使HOXD基因座中長(zhǎng)約40kb的區(qū)域發(fā)生轉(zhuǎn)錄沉默。目前認(rèn)為HOTAIR執(zhí)行的作用機(jī)制是：多梳染色質(zhì)重塑復(fù)合物具有操縱細(xì)胞表觀遺傳狀態(tài)的功能，而HOTAIR以反式調(diào)控的方式指導(dǎo)該功能的發(fā)揮并繼而影響基因的表達(dá)。多梳復(fù)合物中的成員包括SUZ12、EZH2和EED等，它們具有RNA結(jié)合結(jié)構(gòu)域并可能結(jié)合HOTAIR及其它類似的非編碼RNA類（Denisenko 1998；Katayama 2005）。該例子極好地描繪出了這樣一個(gè)更廣泛的主題：非編碼RNA類招募一系列染色質(zhì)修飾蛋白到特定基因組基因座上并發(fā)揮功能，這更加突出了目前所繪制基因組圖譜的復(fù)雜性（Mikkelsen 2007）。發(fā)育時(shí)期中調(diào)控基因表達(dá)的染色質(zhì)修飾有著區(qū)域化的模式，大量長(zhǎng)鏈非編碼與蛋白編碼基因的聯(lián)系確實(shí)幫助塑造了這種模式。例如，大多數(shù)蛋白編碼基因都具有配對(duì)的反義基因，許多抑癌基因在癌癥中常受到沉默，一些反義基因使用表觀遺傳機(jī)制使這些抑癌基因沉默（Yu 2008）。近期研究發(fā)現(xiàn)：在白血病中p15基因和一條反義非編碼RNA的表達(dá)此消彼長(zhǎng)（Yu 2008）。經(jīng)過(guò)詳細(xì)分析發(fā)現(xiàn)：p15的反義非編碼RNA（CDKN2BAS）可通過(guò)一種未知機(jī)制誘導(dǎo)p15的異染色質(zhì)和DNA甲基化狀態(tài)發(fā)生改變，因而調(diào)控了p15基因的表達(dá)（Yu 2008）。因此，相關(guān)的反義非編碼RNA類表達(dá)發(fā)生異常可能繼而沉默了抑癌基因，從而走向癌癥發(fā)生。

基因印記

最近非編碼RNA指導(dǎo)的染色質(zhì)修飾主題最初是從基因組印記的現(xiàn)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(gè)表達(dá)出等位基因的現(xiàn)象。一般來(lái)說(shuō)，印記基因是呈簇狀排列于染色體上，這提示：印記的機(jī)制是作用于局部的染色質(zhì)區(qū)域上而不是針對(duì)單個(gè)基因。這些基因簇常常與長(zhǎng)鏈非編碼RNA相關(guān)：長(zhǎng)鏈非編碼RNA的表達(dá)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(guān)（Pauler 2007）。詳細(xì)分析確實(shí)顯示出非編碼RNA Kcnqot1和Igf2r/Air在指導(dǎo)基因印記上發(fā)揮著重要作用（Braidotti 2004）。

幾乎所有位于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.

長(zhǎng)鏈非編碼RNA類在衰老與疾病中的作用

外部鏈接

另見(jiàn)

參考文獻(xiàn)

  • Allen E, Xie Z, Gustafson AM, Sung GH, Spatafora JW, Carrington JC. Evolution of microRNA genes by inverted duplication of target gene sequences in Arabidopsis thaliana. Nature Genetics. December 2004, 36 (12): 1282–90. doi:10.1038/ng1478. PMID 15565108. 
  • PubMed
  • Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science. November 2007, 318 (5851): 798–801. doi:10.1126/science.1147182. PMID 17916692. 
  • Beltran M, Puig I, Pe?a C, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2275429/ A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition]. Genes & Development. March 2008, 22 (6): 756–69. doi:10.1101/gad.455708. PMID 18347095. PMC 2275429. 
  • Bentwich I, Avniel A, Karov Y, et al.. Identification of hundreds of conserved and nonconserved human microRNAs. Nature Genetics. July 2005, 37 (7): 766–70. doi:10.1038/ng1590. PMID 15965474. 
  • Birney E, Stamatoyannopoulos JA, Dutta A, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2212820/ Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project]. Nature. June 2007, 447 (7146): 799–816. doi:10.1038/nature05874. PMID 17571346. PMC 2212820. 
  • Blasco MA. Telomere length, stem cells and aging. Nature Chemical Biology. October 2007, 3 (10): 640–9. doi:10.1038/nchembio.2007.38. PMID 17876321. 
  • Braidotti G, Baubec T, Pauler F, et al.. The Air noncoding RNA: an imprinted cis-silencing transcript. Cold Spring Harbor Symposia on Quantitative Biology. 2004, 69: 55–66. doi:10.1101/sqb.2004.69.55. PMID 16117633. 
  • Broadbent HM, Peden JF, Lorkowski S, et al.. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Human Molecular Genetics. 2008, 17 (6): 806–14. doi:10.1093/hmg/ddm352. PMID 18048406. 
  • Brosius J. Waste not, want not--transcript excess in multicellular eukaryotes. Trends in Genetics. May 2005, 21 (5): 287–8. doi:10.1016/j.tig.2005.02.014. PMID 15851065. 
  • Calin GA, Liu CG, Ferracin M, et al.. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell. September 2007, 12 (3): 215–29. doi:10.1016/j.ccr.2007.07.027. PMID 17785203. 
  • Carninci P, Kasukawa T, Katayama S, et al.. The transcriptional landscape of the mammalian genome. Science. September 2005, 309 (5740): 1559–63. doi:10.1126/science.1112014. PMID 16141072. 
  • Centonze D, Rossi S, Napoli I, et al.. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. The Journal of Neuroscience. August 2007, 27 (33): 8885–92. doi:10.1523/JNEUROSCI.0548-07.2007. PMID 17699670. 
  • Chen X, Xu H, Yuan P, et al.. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. June 2008, 133 (6): 1106–17. doi:10.1016/j.cell.2008.04.043. PMID 18555785. 
  • Cheng J, Kapranov P, Drenkow J, et al.. Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science. May 2005, 308 (5725): 1149–54. doi:10.1126/science.1108625. PMID 15790807. 
  • Costanzi C, Pehrson JR. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature. June 1998, 393 (6685): 599–601. doi:10.1038/31275. PMID 9634239. 
  • Czech B, Malone CD, Zhou R, et al.. An endogenous small interfering RNA pathway in Drosophila. Nature. June 2008, 453 (7196): 798–802. doi:10.1038/nature07007. PMID 18463631. 
  • Denisenko O, Shnyreva M, Suzuki H, Bomsztyk K. Point mutations in the WD40 domain of Eed block its interaction with Ezh2. Molecular and Cellular Biology. 1 October 1998, 18 (10): 5634–42. PMID 9742080. PMC 109149. 
  • PubMed
  • Dieci G, Fiorino G, Castelnuovo M, Teichmann M, Pagano A. The expanding RNA polymerase III transcriptome. Trends in Genetics. December 2007, 23 (12): 614–22. doi:10.1016/j.tig.2007.09.001. PMID 17977614. 
  • PubMed
  • Eis PS, Tam W, Sun L, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC552785/ Accumulation of miR-155 and BIC RNA in human B cell lymphomas]. Proceedings of the National Academy of Sciences of the United States of America. March 2005, 102 (10): 3627–32. doi:10.1073/pnas.0500613102. PMID 15738415. PMC 552785. 
  • Espinoza CA, Allen TA, Hieb AR, Kugel JF, Goodrich JA. B2 RNA binds directly to RNA polymerase II to repress transcript synthesis. Nature Structural & Molecular Biology. September 2004, 11 (9): 822–9. doi:10.1038/nsmb812. PMID 15300239. 
  • Espinoza CA, Goodrich JA, Kugel JF. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1831867/ Characterization of the structure, function, and mechanism of B2 RNA, an ncRNA repressor of RNA polymerase II transcription]. RNA. April 2007, 13 (4): 583–96. doi:10.1261/rna.310307. PMID 17307818. PMC 1831867. 
  • Faghihi MA, Modarresi F, Khalil AM, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2826895/ Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase]. Nature Medicine. July 2008, 14 (7): 723–30. doi:10.1038/nm1784. PMID 18587408. PMC 2826895. 
  • Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1475760/ The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator]. Genes & Development. June 2006, 20 (11): 1470–84. doi:10.1101/gad.1416106. PMID 16705037. PMC 1475760. 
  • Fournier C, Goto Y, Ballestar E, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC136958/ Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes]. The EMBO Journal. December 2002, 21 (23): 6560–70. doi:10.1093/emboj/cdf655. PMID 12456662. PMC 136958. 
  • Fu X, Ravindranath L, Tran N, Petrovics G, Srivastava S. Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1. DNA and Cell Biology. March 2006, 25 (3): 135–41. doi:10.1089/dna.2006.25.135. PMID 16569192. 
  • Golden DE, Gerbasi VR, Sontheimer EJ. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2675693/ An inside job for siRNAs]. Molecular Cell. August 2008, 31 (3): 309–12. doi:10.1016/j.molcel.2008.07.008. PMID 18691963. PMC 2675693. 
  • Goodrich JA, Kugel JF. Non-coding-RNA regulators of RNA polymerase II transcription. Nature Reviews Molecular Cell Biology. August 2006, 7 (8): 612–6. doi:10.1038/nrm1946. PMID 16723972. 
  • Hesman Saey, Tina. Missing Lincs. Science News. 17 December 2011, 180 (13): 22–25. 
  • Ishii N, Ozaki K, Sato H, et al.. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. Journal of Human Genetics. 2006, 51 (12): 1087–99. doi:10.1007/s10038-006-0070-9. PMID 17066261. 
  • Jarinova O, Stewart AF, Roberts R, et al.. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arteriosclerosis, Thrombosis, and Vascular Biology. October 2009, 29 (10): 1671–77. doi:10.1161/ATVBAHA.109.189522. PMID 19592466. 
  • Kapranov P, Cheng J, Dike S, et al.. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. June 2007, 316 (5830): 1484–8. doi:10.1126/science.1138341. PMID 17510325. 
  • Kapranov P, Willingham AT, Gingeras TR. Genome-wide transcription and the implications for genomic organization. Nature Reviews. Genetics. June 2007, 8 (6): 413–23. doi:10.1038/nrg2083. PMID 17486121. 
  • Kapranov P, St Laurent G, Raz T, et al.. The majority of total nuclear-encoded non-ribosomal RNA in a human cell is 'dark matter' un-annotated RNA. BMC Biol.. 2010, 8: 149. doi:10.1186/1741-7007-8-149. PMID 21176148. PMC 3022773.  Erratum in: BMC Biol. 2011;9:86.
  • Katayama S, Tomaru Y, Kasukawa T, et al.. Antisense transcription in the mammalian transcriptome. Science. September 2005, 309 (5740): 1564–6. doi:10.1126/science.1112009. PMID 16141073. 
  • Kiefer JC. Epigenetics in development. Developmental Dynamics. April 2007, 236 (4): 1144–56. doi:10.1002/dvdy.21094. PMID 17304537. 
  • Kim. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2811656/ Evidence for bacterial origin of heat shock RNA-1]. RNA. February 2010, 16 (2): 274–279. doi:10.1261/rna.1879610. PMID 20040589. PMC 2811656. 
  • Kwek KY, Murphy S, Furger A, et al.. U1 snRNA associates with TFIIH and regulates transcriptional initiation. Nature Structural Biology. November 2002, 9 (11): 800–5. doi:10.1038/nsb862. PMID 12389039. 
  • Lander ES, Linton LM, Birren B, et al.. Initial sequencing and analysis of the human genome. Nature. February 2001, 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011. 
  • Lee JS, Burkholder GD, Latimer LJ, Haug BL, Braun RP. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC340507/ A monoclonal antibody to triplex DNA binds to eucaryotic chromosomes]. Nucleic Acids Research. February 1987, 15 (3): 1047–61. doi:10.1093/nar/15.3.1047. PMID 2434928. PMC 340507. 
  • Lewejohann L, Skryabin BV, Sachser N, et al.. Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice. Behavioural Brain Research. September 2004, 154 (1): 273–89. doi:10.1016/j.bbr.2004.02.015. PMID 15302134. 
  • Li J, Witte DP, Van Dyke T, Askew DS. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1858164/ Expression of the putative proto-oncogene His-1 in normal and neoplastic tissues]. The American Journal of Pathology. April 1997, 150 (4): 1297–305. PMID 9094986. PMC 1858164. 
  • Lin R, Maeda S, Liu C, Karin M, Edgington TS. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene. February 2007, 26 (6): 851–8. doi:10.1038/sj.onc.1209846. PMID 16878148. 
  • lincRNA homepage of the Rinn Lab
  • Liu WM, Chu WM, Choudary PV, Schmid CW. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC306933/ Cell stress and translational inhibitors transiently increase the abundance of mammalian SINE transcripts]. Nucleic Acids Research. May 1995, 23 (10): 1758–65. doi:10.1093/nar/23.10.1758. PMID 7784180. PMC 306933. 
  • Liu Y, Sanoff HK, Cho H, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2660422/ INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis]. PloS One. April 2009, 4 (4): e5027. doi:10.1371/journal.pone.0005027. PMID 19343170. PMC 2660422. 
  • Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1472902/ Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes]. Genes & Development. May 2006, 20 (10): 1268–82. doi:10.1101/gad.1416906. PMID 16702402. PMC 1472902. 
  • Mariner PD, Walters RD, Espinoza CA, et al.. Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Molecular Cell. February 2008, 29 (4): 499–509. doi:10.1016/j.molcel.2007.12.013. PMID 18313387. 
  • Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature. February 2007, 445 (7128): 666–70. doi:10.1038/nature05519. PMID 17237763. 
  • Mattick JS. Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays. October 2003, 25 (10): 930–9. doi:10.1002/bies.10332. PMID 14505360. 
  • Mazo A, Hodgson JW, Petruk S, Sedkov Y, Brock HW. Transcriptional interference: an unexpected layer of complexity in gene regulation. Journal of Cell Science. August 2007, 120 (Pt 16): 2755–61. doi:10.1242/jcs.007633. PMID 17690303. 
  • McPherson R, Pertsemlidis A, Kavaslar N , et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2711874/ A Common Allele on Chromosome 9 Associated with Coronary Heart Disease]. Science. May 2007, 316 (5830): 1488–91. doi:10.1126/science.1142447. PMID 17478681. PMC 2711874. 
  • PubMed
  • Mikkelsen TS, Ku M, Jaffe DB, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2921165/ Genome-wide maps of chromatin state in pluripotent and lineage-committed cells]. Nature. August 2007, 448 (7153): 553–60. doi:10.1038/nature06008. PMID 17603471. PMC 2921165. 
  • Mitsuya K, Meguro M, Lee MP, et al.. LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids. Human Molecular Genetics. July 1999, 8 (7): 1209–17. doi:10.1093/hmg/8.7.1209. PMID 10369866. 
  • Mohammad F, Pandey RR, Nagano T, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2423283/ Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region]. Molecular and Cellular Biology. June 2008, 28 (11): 3713–28. doi:10.1128/MCB.02263-07. PMID 18299392. PMC 2423283. 
  • Morey C, Navarro P, Debrand E, Avner P, Rougeulle C, Clerc P. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1271805/ The region 3' to Xist mediates X chromosome counting and H3 Lys-4 dimethylation within the Xist gene]. The EMBO Journal. February 2004, 23 (3): 594–604. doi:10.1038/sj.emboj.7600071. PMID 14749728. PMC 1271805. 
  • Munroe SH, Lazar MA. Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA. The Journal of Biological Chemistry. 25 November 1991, 266 (33): 22083–6. PMID 1657988. 
  • Muslimov IA, Banker G, Brosius J, Tiedge H. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1828539/ Activity-dependent regulation of dendritic BC1 RNA in hippocampal neurons in culture]. The Journal of Cell Biology. June 1998, 141 (7): 1601–11. doi:10.1083/jcb.141.7.1601. PMID 9647652. PMC 1828539. 
  • Nesterova TB, Barton SC, Surani MA, Brockdorff N. Loss of Xist imprinting in diploid parthenogenetic preimplantation embryos. Developmental Biology. July 2001, 235 (2): 343–50. doi:10.1006/dbio.2001.0295. PMID 11437441. 
  • Nickerson JA, Krochmalnic G, Wan KM, Penman S. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC286427/ Chromatin architecture and nuclear RNA]. Proceedings of the National Academy of Sciences of the United States of America. January 1989, 86 (1): 177–81. doi:10.1073/pnas.86.1.177. PMID 2911567. PMC 286427. 
  • Ogawa Y, Sun BK, Lee JT. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2584363/ Intersection of the RNA interference and X-inactivation pathways]. Science. June 2008, 320 (5881): 1336–41. doi:10.1126/science.1157676. PMID 18535243. PMC 2584363. 
  • Pagano JM, Farley BM, McCoig LM, Ryder SP. Molecular basis of RNA recognition by the embryonic polarity determinant MEX-5. The Journal of Biological Chemistry. March 2007, 282 (12): 8883–94. doi:10.1074/jbc.M700079200. PMID 17264081. 
  • Pang KC, Frith MC, Mattick JS. Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends in Genetics. January 2006, 22 (1): 1–5. doi:10.1016/j.tig.2005.10.003. PMID 16290135. 
  • Panganiban G, Rubenstein JL. Developmental functions of the Distal-less/Dlx homeobox genes. Development. 1 October 2002, 129 (19): 4371–86. PMID 12223397. 
  • Pasmant E, Laurendeau I, Héron D, Vidaud M, Vidaud D, Bièche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Research. April 2007, 67 (8): 3963–9. doi:10.1158/0008-5472.CAN-06-2004. PMID 17440112. 
  • Pauler FM, Koerner MV, Barlow DP. Silencing by imprinted noncoding RNAs: is transcription the answer?. Trends in Genetics. June 2007, 23 (6): 284–92. doi:10.1016/j.tig.2007.03.018. PMID 17445943. 
  • Pennacchio LA, Ahituv N, Moses AM, et al.. In vivo enhancer analysis of human conserved non-coding sequences. Nature. November 2006, 444 (7118): 499–502. doi:10.1038/nature05295. PMID 17086198. 
  • Perkel, Jeffrey M.. Visiting "Noncodarnia" (paper). BioTechniques. 2013, 54 (6): 301–304. doi:10.2144/000114037. PMID 23750541. ""We're calling long noncoding RNAs a class, when actually the only definition is that they are longer than 200 bp," says Ana Marques, a Research Fellow at the University of Oxford who uses evolutionary approaches to understand lncRNA function." 
  • Pibouin L, Villaudy J, Ferbus D, et al.. Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas. Cancer Genetics and Cytogenetics. February 2002, 133 (1): 55–60. doi:10.1016/S0165-4608(01)00634-3. PMID 11890990. 
  • Pollard KS, Salama SR, King B, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1599772/ Forces shaping the fastest evolving regions in the human genome]. PLoS Genetics. October 2006, 2 (10): e168. doi:10.1371/journal.pgen.0020168. PMID 17040131. PMC 1599772. 
  • Pollard KS, Salama SR, Lambert N, et al.. An RNA gene expressed during cortical development evolved rapidly in humans. Nature. September 2006, 443 (7108): 167–72. doi:10.1038/nature05113. PMID 16915236. 
  • Ponjavic J, Ponting CP, Lunter G. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1855172/ Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs]. Genome Research. May 2007, 17 (5): 556–65. doi:10.1101/gr.6036807. PMID 17387145. PMC 1855172. 
  • PubMed
  • Reis EM, Nakaya HI, Louro R, et al.. Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer. Oncogene. August 2004, 23 (39): 6684–92. doi:10.1038/sj.onc.1207880. PMID 15221013. 
  • Rinn JL, Kertesz M, Wang JK, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2084369/ Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs]. Cell. June 2007, 129 (7): 1311–23. doi:10.1016/j.cell.2007.05.022. PMID 17604720. PMC 2084369. 
  • Rodríguez-Campos A, Azorín F. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2063516/ RNA is an integral component of chromatin that contributes to its structural organization]. PLoS ONE. 2007, 2 (11): e1182. doi:10.1371/journal.pone.0001182. PMID 18000552. PMC 2063516. 
  • Sanchez-Elsner T, Gou D, Kremmer E, Sauer F. Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to Ultrabithorax. Science. February 2006, 311 (5764): 1118–23. doi:10.1126/science.1117705. PMID 16497925. 
  • Schoeftner S, Blasco MA. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nature Cell Biology. February 2008, 10 (2): 228–36. doi:10.1038/ncb1685. PMID 18157120. 
  • Shamovsky I, Nudler E. Gene control by large noncoding RNAs. Science's STKE : Signal Transduction Knowledge Environment. October 2006, 2006 (355): pe40. doi:10.1126/stke.3552006pe40. PMID 17018852. 
  • Shamovsky I, Nudler E. Modular RNA heats up. Molecular Cell. February 2008, 29 (4): 415–7. doi:10.1016/j.molcel.2008.02.001. PMID 18313380. 
  • Shirasawa S, Harada H, Furugaki K, et al.. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. Human Molecular Genetics. October 2004, 13 (19): 2221–31. doi:10.1093/hmg/ddh245. PMID 15294872. 
  • Siepel A, Bejerano G, Pedersen JS, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1182216/ Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes]. Genome Research. August 2005, 15 (8): 1034–50. doi:10.1101/gr.3715005. PMID 16024819. PMC 1182216. 
  • Singh K, Carey M, Saragosti S, Botchan M. Expression of enhanced levels of small RNA polymerase III transcripts encoded by the B2 repeats in simian virus 40-transformed mouse cells. Nature. 1985, 314 (6011): 553–6. doi:10.1038/314553a0. PMID 2581137. 
  • Sleutels F, Zwart R, Barlow DP. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature. February 2002, 415 (6873): 810–3. doi:10.1038/415810a. PMID 11845212. 
  • Smith NG, Brandstr?m M, Ellegren H. Evidence for turnover of functional noncoding DNA in mammalian genome evolution. Genomics. November 2004, 84 (5): 806–13. doi:10.1016/j.ygeno.2004.07.012. PMID 15475259. 
  • Sonkoly E, Bata-Csorgo Z, Pivarcsi A, et al.. Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS. The Journal of Biological Chemistry. June 2005, 280 (25): 24159–67. doi:10.1074/jbc.M501704200. PMID 15855153. 
  • Struhl K. Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nature Structural & Molecular Biology. February 2007, 14 (2): 103–5. doi:10.1038/nsmb0207-103. PMID 17277804. 
  • Tang RB, Wang HY, Lu HY, et al.. Increased level of polymerase III transcribed Alu RNA in hepatocellular carcinoma tissue. Molecular Carcinogenesis. February 2005, 42 (2): 93–6. doi:10.1002/mc.20057. PMID 15593371. 
  • Tiedge H, Chen W, Brosius J. Primary structure, neural-specific expression, and dendritic location of human BC200 RNA. Journal of Neuroscience. 1 June 1993, 13 (6): 2382–90. PMID 7684772. 
  • Tiedge H, Fremeau RT, Weinstock PH, Arancio O, Brosius J. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC51175/ Dendritic location of neural BC1 RNA]. Proceedings of the National Academy of Sciences of the United States of America. March 1991, 88 (6): 2093–7. doi:10.1073/pnas.88.6.2093. PMID 1706516. PMC 51175. 
  • Torarinsson E, Sawera M, Havgaard JH, Fredholm M, Gorodkin J. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1484455/ Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure]. Genome Research. July 2006, 16 (7): 885–9. doi:10.1101/gr.5226606. PMID 16751343. PMC 1484455. 
  • Torarinsson E, Sawera M, Havgaard JH, Fredholm M, Gorodkin J. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1484455/ Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure]. Genome Research. July 2006, 16 (7): 885–9. doi:10.1101/gr.5226606. PMID 16751343. PMC 1484455. 
  • Tufarelli C, Stanley JA, Garrick D, et al.. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nature Genetics. June 2003, 34 (2): 157–65. doi:10.1038/ng1157. PMID 12730694. 
  • Umlauf D, Goto Y, Cao R, et al.. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nature Genetics. December 2004, 36 (12): 1296–300. doi:10.1038/ng1467. PMID 15516932. 
  • Visel A, Prabhakar S, Akiyama JA, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2647775/ Ultraconservation identifies a small subset of extremely constrained developmental enhancers]. Nature Genetics. February 2008, 40 (2): 158–60. doi:10.1038/ng.2007.55. PMID 18176564. PMC 2647775. 
  • Wang H, Iacoangeli A, Lin D, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1828541/ Dendritic BC1 RNA in translational control mechanisms]. The Journal of Cell Biology. December 2005, 171 (5): 811–21. doi:10.1083/jcb.200506006. PMID 16330711. PMC 1828541. 
  • Wang X, Arai S, Song X, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2823488/ Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription]. Nature. July 2008, 454 (7200): 126–30. doi:10.1038/nature06992. PMID 18509338. PMC 2823488. 
  • Waterston RH, Lindblad-Toh K, Birney E, et al.. Initial sequencing and comparative analysis of the mouse genome. Nature. December 2002, 420 (6915): 520–62. doi:10.1038/nature01262. PMID 12466850. 
  • Wutz A, Gribnau J. X inactivation Xplained. Current Opinion in Genetics & Development. October 2007, 17 (5): 387–93. doi:10.1016/j.gde.2007.08.001. PMID 17869504. 
  • Wutz A, Rasmussen TP, Jaenisch R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nature Genetics. February 2002, 30 (2): 167–74. doi:10.1038/ng820. PMID 11780141. 
  • Yang S, Tutton S, Pierce E, Yoon K. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC99950/ Specific double-stranded RNA interference in undifferentiated mouse embryonic stem cells]. Molecular and Cellular Biology. November 2001, 21 (22): 7807–16. doi:10.1128/MCB.21.22.7807-7816.2001. PMID 11604515. PMC 99950. 
  • Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Molecular Cell. October 2003, 12 (4): 971–82. doi:10.1016/S1097-2765(03)00388-5. PMID 14580347. 
  • Yu W, Gius D, Onyango P, et al.. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2743558/ Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA]. Nature. January 2008, 451 (7175): 202–6. doi:10.1038/nature06468. PMID 18185590. PMC 2743558. 
  • Zearfoss NR, Chan AP, Kloc M, Allen LH, Etkin LD. Identification of new Xlsirt family members in the Xenopus laevis oocyte. Mechanisms of Development. April 2003, 120 (4): 503–9. doi:10.1016/S0925-4773(02)00459-8. PMID 12676327. 
  • Zwart R, Sleutels F, Wutz A, Schinkel AH, Barlow DP. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC312779/ Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes]. Genes & Development. September 2001, 15 (18): 2361–6. doi:10.1101/gad.206201. PMID 11562346. PMC 312779. 


蛋白質(zhì)生物合成
RNA加工
小核RNA（snRNA） · 小核仁RNA（snoRNA） · 向?qū)NA（gRNA） · RNA酶P · RNA酶MRP · Y RNA
基因表達(dá)調(diào)控
反義RNA · 順式天然反義轉(zhuǎn)錄本（cis-NAT） · CRISPR RNA（crRNA） · 長(zhǎng)鏈非編碼RNA · 小分子RNA（miRNA） · 基因沉默小RNA（piRNA） · 重復(fù)相關(guān)干擾小RNA（rasiRNA） · 小干擾RNA（siRNA） · 小時(shí)序RNA（stRNA） · 反式作用干擾小RNA（tasiRNA）
順式調(diào)控元件
寄生
其他

參考來(lái)源

關(guān)于“長(zhǎng)鏈非編碼RNA”的留言： Feed-icon.png 訂閱討論RSS

目前暫無(wú)留言

添加留言

更多醫(yī)學(xué)百科條目

個(gè)人工具
名字空間
動(dòng)作
導(dǎo)航
推薦工具
功能菜單
工具箱
亚洲国产成人久久综合三区,97国产精品传媒在线观看,国产成人一区二区在线视频导航,无码一区二区三区在线观看
亚洲狠狠婷婷综合久久久久 | 亚洲一区在线国产 | 在线综合亚洲欧美日韩 | 色窝窝视频手机在线播放 | 尤物欧美一区二区 | 午夜福利中文字幕有码 |