Xist RNA antagonizes the SWI/SNF chromatin remodeler BRG1 on the inactive X chromosome

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. Interestingly, Xist deletion triggers a gain of accessibility of selective 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 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.