PAR-TERRA directs homologous sex chromosome pairing

In mammals, homologous chromosomes rarely pair outside of meiosis. An exception is the X-chromosome, which transiently pairs during X-chromosome inactivation (XCI). How two chromosomes find each other in 3D space is not known. Here, we reveal a required interaction between the X-inactivation center (Xic) and the telomere in mouse embryonic stem cells. The sub-telomeric, pseudoautosomal region (PAR) of both sex chromosomes (X,Y) also undergoes pairing. PAR transcribes a class of telomeric RNA, dubbed “PAR-TERRA”, which accounts for a vast majority of all TERRA transcripts. PAR-TERRA binds throughout the genome, including PAR and Xic. PAR-TERRA anchors the Xic to PAR, creating a “tetrad” of pairwise homologous interactions (Xic:Xic, PAR:PAR, Xic:PAR). Xic pairing occurs within the tetrad. Depleting PAR-TERRA abrogates pairing and blocks initiation of XCI, whereas autosomal PAR-TERRA induces ectopic pairing. We proposed a Constrained Diffusion Model in which PAR-TERRA creates an interaction hub to guide Xic homology searching during XCI.