Howard Hughes Medical Institute, Boston, MA, USA.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
Nat Struct Mol Biol. 2019 Feb;26(2):96-109. doi: 10.1038/s41594-018-0176-8. Epub 2019 Jan 21.
The noncoding RNA Xist recruits silencing factors to the inactive X chromosome (Xi) and facilitates re-organization of Xi structure. Here, we examine the mouse epigenomic landscape of Xi and assess how Xist alters chromatin accessibility. Xist deletion triggers a gain of accessibility of select chromatin regions that is regulated by BRG1, an ATPase subunit of the SWI/SNF chromatin-remodeling complex. In vitro, RNA binding inhibits nucleosome-remodeling and ATPase activities of BRG1, while in cell culture Xist directly interacts with BRG1 and expels BRG1 from the Xi. Xist ablation leads to a selective return of BRG1 in cis, starting from pre-existing BRG1 sites that are free of Xist. BRG1 re-association correlates with cohesin binding and restoration of topologically associated domains (TADs) and results in the formation of de novo Xi 'superloops'. Thus, Xist binding inhibits BRG1's nucleosome-remodeling activity and results in expulsion of the SWI/SNF complex from the Xi.
非编码 RNA Xist 将沉默因子招募到失活 X 染色体 (Xi) 上，并促进 Xi 结构的重新组织。在这里，我们研究了小鼠 Xi 的表观基因组景观，并评估了 Xist 如何改变染色质可及性。Xist 的缺失触发了一些染色质区域的可及性增加，这些区域受 SWI/SNF 染色质重塑复合物的 ATP 酶亚基 BRG1 调控。在体外，RNA 结合抑制 BRG1 的核小体重塑和 ATP 酶活性，而在细胞培养中，Xist 直接与 BRG1 相互作用，并将 BRG1 从 Xi 中驱逐出去。Xist 的缺失导致 BRG1 从 cis 选择性地回归，从没有 Xist 的预先存在的 BRG1 位点开始。BRG1 的重新结合与黏连蛋白的结合以及拓扑相关结构域 (TAD) 的恢复相关，并导致新形成的 Xi '超级环'。因此，Xist 的结合抑制了 BRG1 的核小体重塑活性，并导致 SWI/SNF 复合物从 Xi 中被驱逐。
