Large noncoding RNAs (lncRNAs) are increasingly appreciated to play important roles in the cell. A number of lncRNAs act to target chromatin regulatory complexes to their sites of action. Here we found that the mouse Xist lncRNA, which initiates X-chromosome inactivation, spreads from its site of transcription to distant sites on the X chromosome purely through their close three-dimensional proximity to the Xist gene. upon distal spread, Xist initially localizes to the periphery of active genes on the X chromosome but gradually spread across them using its A-repeat domain, until the Xist RNA bound broadly across the inactive X chromosome in differentiated female cells. Our work reveals an important mechanism that explains how Xist RNA initiates X chromosome inactivation.
Many large noncoding RNAs (lncRNAs) regulate chromatin, but the mechanisms by which they localize to genomic targets remain unexplored. We investigated the localization mechanisms of the Xist lncRNA during X-chromosome inactivation (XCI), a paradigm of lncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the three-dimensional conformation of the X chromosome. Xist requires its silencing domain to spread across actively transcribed regions and thereby access the entire chromosome. These findings suggest a model in which Xist coats the X chromosome by searching in three dimensions, modifying chromosome structure, and spreading to newly accessible locations.