Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature. 2011 Aug 28;477(7364):295-300. doi: 10.1038/nature10398.
Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.
虽然哺乳动物中已经鉴定出数千种大型基因间非编码 RNA(lincRNA)，但很少有其功能得到明确鉴定，这导致了对其生物学作用的争议。为了解决这个问题，我们对在小鼠胚胎干细胞(ES 细胞)中表达的大多数 lincRNA 进行了功能丧失研究，并对其对基因表达的影响进行了特征描述。在这里，我们表明 lincRNA 的敲低对基因表达模式有重大影响，与众所周知的 ES 细胞调节剂的敲低相当。值得注意的是，lincRNA 主要在转录间影响基因表达。数十种 lincRNA 的敲低会导致细胞退出多能状态或上调谱系分化程序。我们将 lincRNA 整合到 ES 细胞的分子电路中，并表明 lincRNA 基因受关键转录因子调控，并且 lincRNA 转录本与多种染色质调节蛋白结合，以影响共享的基因表达程序。总之，这些结果表明 lincRNA 在控制 ES 细胞状态的电路中具有关键作用。
