Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression
Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression
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DOI：
10.1073/pnas.0904715106
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发表时间：
2009-07-14
影响因子：
11.1
通讯作者：
Rinn, John L.
中科院分区：
文献类型：
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作者：
Khalil, Ahmad M.;Guttman, Mitchell;Rinn, John L.
我们最近表明，哺乳动物基因组编码超过1，000个大型基因间非编码（linc）RNA，这些RNA在哺乳动物中明显保守，因此具有功能。这些lincRNA的基因表达模式涉及多种生物过程，包括细胞周期调控、免疫监视和胚胎干细胞多能性。然而，这些lincRNA发挥作用的机制尚不清楚。在这里，我们通过分析各种人类细胞类型的染色质状态图，将人类lincRNA的目录扩展到大约3,300个。受到充分表征的lincRNA HOTAIR结合多梳阻遏复合物（PRC）2的观察的启发，我们测试了许多lincRNA是否与PRC 2物理相关。值得注意的是，我们观察到在各种细胞类型中表达的lincRNA的约20%被PRC 2结合，并且另外的lincRNA被其他染色质修饰复合物结合。此外，我们表明，与PRC 2相关的某些lincRNA的siRNA介导的耗竭导致基因表达的变化，并且上调的基因富集了那些通常被PRC 2沉默的基因。我们提出了一个模型，其中一些lincRNA引导染色质修饰复合物到特定的基因组位点来调节基因表达。
We recently showed that the mammalian genome encodes >1,000 large intergenic noncoding (linc) RNAs that are clearly conserved across mammals and, thus, functional. Gene expression patterns have implicated these lincRNAs in diverse biological processes, including cell-cycle regulation, immune surveillance, and embryonic stem cell pluripotency. However, the mechanism by which these lincRNAs function is unknown. Here, weexpand the catalog of human lincRNAs to approximate to 3,300 by analyzing chromatin-state maps of various human cell types. Inspired by the observation that the well-characterized lincRNA HOTAIR binds the polycomb repressive complex (PRC) 2, we tested whether many lincRNAs are physically associated with PRC2. Remarkably, we observe that approximate to 20% of lincRNAs expressed in various cell types are bound by PRC2, and that additional lincRNAs are bound by other chromatin-modifying complexes. Also, we show that siRNA-mediated depletion of certain lincRNAs associated with PRC2 leads to changes in gene expression, and that the up-regulated genes are enriched for those normally silenced by PRC2. We propose a model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression.