R loops regulate promoter-proximal chromatin architecture and cellular differentiation.
R loops regulate promoter-proximal chromatin architecture and cellular differentiation.
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DOI：
10.1038/nsmb.3122
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发表时间：
2015-12
影响因子：
16.8
通讯作者：
Fazzio TG
中科院分区：
文献类型：
--
作者：
Chen PB;Chen HV;Acharya D;Rando OJ;Fazzio TG
许多染色质重塑因子通过与RNA的相互作用来调节，尽管RNA结合的背景和功能尚不清楚。在这里，我们展示了r环，RNA:DNA杂交组成的新生转录物与模板DNA杂交，调节小鼠胚胎干细胞（ESCs）中两个关键染色质调节复合物Tip60-p400和多梳抑制复合物2 （PRC2）的结合。与PRC2一样，Tip60-p400组蛋白乙酰转移酶复合物与新生转录物结合，但与PRC2不同的是，转录促进了Tip60-p400与染色质的结合。有趣的是，我们在启动子-近端r环标记的基因中观察到较高的Tip60-p400和较低的PRC2水平。此外，r环的破坏广泛降低了Tip60-p400，增加了PRC2全基因组的占用。与这些改变一致，r环减少的ESCs表现出分化受损。这些结果表明，r -环在调节关键多能性调控因子的募集过程中既有积极的作用，也有消极的作用。
Numerous chromatin-remodeling factors are regulated by interactions with RNA, although the contexts and functions of RNA binding are poorly understood. Here we show that R-loops, RNA:DNA hybrids consisting of nascent transcripts hybridized to template DNA, modulate the binding of two key chromatin regulatory complexes, Tip60–p400 and polycomb repressive complex 2 (PRC2) in mouse embryonic stem cells (ESCs). Like PRC2, the Tip60–p400 histone acetyltransferase complex binds to nascent transcripts, but unlike PRC2, transcription promotes chromatin binding by Tip60–p400. Interestingly, we observed higher Tip60–p400 and lower PRC2 levels at genes marked by promoter-proximal R-loops. Furthermore, disruption of R-loops broadly reduced Tip60–p400 and increased PRC2 occupancy genome-wide. Consistent with these alterations, ESCs with reduced R-loops exhibited impaired differentiation. These results show that R-loops act both positively and negatively to modulate the recruitment of key pluripotency regulators.