The study investigates the mechanisms by which the long noncoding RNA (lncRNA) Xist localizes to and spreads across the X chromosome during X-chromosome inactivation (XCI). Using a method called RNA Antisense Purification (RAP), the authors found that Xist binds broadly across the entire X chromosome in differentiated female cells, preferentially at gene-rich regions. During the initiation of XCI, Xist initially localizes to distal regions across the X chromosome, which are defined by their spatial proximity to the Xist transcription locus rather than specific sequence motifs. This initial localization is followed by spreading across actively transcribed regions, facilitated by the A-repeat domain of Xist, which interacts with the polycomb repressive complex 2 (PRC2) and enables chromatin silencing. The study suggests that Xist exploits the three-dimensional conformation of the X chromosome to spread and silence the entire X chromosome, involving a search in three dimensions, modification of chromatin structure, and spreading to new accessible locations.The study investigates the mechanisms by which the long noncoding RNA (lncRNA) Xist localizes to and spreads across the X chromosome during X-chromosome inactivation (XCI). Using a method called RNA Antisense Purification (RAP), the authors found that Xist binds broadly across the entire X chromosome in differentiated female cells, preferentially at gene-rich regions. During the initiation of XCI, Xist initially localizes to distal regions across the X chromosome, which are defined by their spatial proximity to the Xist transcription locus rather than specific sequence motifs. This initial localization is followed by spreading across actively transcribed regions, facilitated by the A-repeat domain of Xist, which interacts with the polycomb repressive complex 2 (PRC2) and enables chromatin silencing. The study suggests that Xist exploits the three-dimensional conformation of the X chromosome to spread and silence the entire X chromosome, involving a search in three dimensions, modification of chromatin structure, and spreading to new accessible locations.