Wellcome Trust Centre for Cell Biology, University of Edinburgh, EH9 3BF Edinburgh, UK; Berlin Institute for Medical Systems Biology, Max Delbrueck Centre for Molecular Medicine, Berlin-Buch 13092, Germany.
Berlin Institute for Medical Systems Biology, Max Delbrueck Centre for Molecular Medicine, Berlin-Buch 13092, Germany.
Mol Cell. 2019 Mar 7;73(5):930-945.e4. doi: 10.1016/j.molcel.2018.12.016. Epub 2019 Jan 29.
R-loops are three-stranded nucleic acid structures that form during transcription, especially over unmethylated CpG-rich promoters of active genes. In mouse embryonic stem cells (mESCs), CpG-rich developmental regulator genes are repressed by the Polycomb complexes PRC1 and PRC2. Here, we show that R-loops form at a subset of Polycomb target genes, and we investigate their contribution to Polycomb repression. At R-loop-positive genes, R-loop removal leads to decreased PRC1 and PRC2 recruitment and Pol II activation into a productive elongation state, accompanied by gene derepression at nascent and processed transcript levels. Stable removal of PRC2 derepresses R-loop-negative genes, as expected, but does not affect R-loops, PRC1 recruitment, or transcriptional repression of R-loop-positive genes. Our results highlight that Polycomb repression does not occur via one mechanism but consists of different layers of repression, some of which are gene specific. We uncover that one such mechanism is mediated by an interplay between R-loops and RING1B recruitment.
R 环是在转录过程中形成的三链核酸结构，特别是在活跃基因的非甲基化 CpG 丰富启动子上。在小鼠胚胎干细胞 (mESC) 中，富含 CpG 的发育调节基因被多梳复合物 PRC1 和 PRC2 抑制。在这里，我们表明 R 环形成在多梳靶基因的一个亚群中，我们研究了它们对多梳抑制的贡献。在 R 环阳性基因中，R 环的去除导致 PRC1 和 PRC2 招募减少和 Pol II 进入生产性延伸状态的激活，伴随着新生和加工转录本水平的基因去抑制。PRC2 的稳定去除如预期的那样使 R 环阴性基因去抑制，但不影响 R 环、PRC1 招募或 R 环阳性基因的转录抑制。我们的结果强调了多梳抑制不是通过一种机制发生的，而是由不同层次的抑制组成，其中一些是基因特异性的。我们发现，其中一种机制是由 R 环和 RING1B 募集之间的相互作用介导的。
