Jpx RNA controls Xist induction through spatial reorganization of the mouse X-inactivation center

Known to regulate chromosome looping on a genome-wide scale, the noncoding Jpx RNA was originally shown to control X chromosome counting and induce Xist expression during X chromosome inactivation (XCI). Not fully understood is how Jpx upregulates Xist in coordination with Tsix downregulation in cis. Here, by integrating epigenomic data and polymer modeling in a mouse embryonic stem cell model, we demonstrate that Jpx controls architectural and transcriptional dynamics within anti- and pro-XCI zones of the X-inactivation center. Distinct topological changes occur on the future active X (Xa) and inactive X (Xi) chromosomes. Jpx binds the enhancer of Tsix on the future Xi and alters loop formation to favor Xist induction, coordinately releasing CTCF from Tsix and Xist in cis on the future Xi. Thus, by controlling a dynamic rewiring of functional loops, Jpx flips a transcriptional switch to control mutually exclusive Tsix and Xist expression in cis.