A Tale of Two Cities: How Xist and its partners localize to and silence the bicompartmental X

•Collapse of active nuclear compartment by Xist RNA binding HnrnpU, evicting RNAPII.•Genome ReOrganization Upon Pluripotency-exit (GRO-UP) acts on Xa/Xi, parallel to XCI.•GRO-UP silences gene-poor, LINE1-rich DNA while Xist localizes to gene-rich islands.•Xist recruits Spen for initial gene silencing, locked in by PRC1/2 and/or macroH2A.•Smchd1 compacts the hypoacetylated Xi across mutually reinforcing H3K9me2/3 & H3K27me3 domains.

Sex chromosomal dosage compensation in mammals takes the form of X chromosome inactivation (XCI), driven by the non-coding RNA Xist. In contrast to dosage compensation systems of flies and worms, mammalian XCI has to restrict its function to the Xist-producing X chromosome, while leaving autosomes and active X untouched. The mechanisms behind the long-range yet cis-specific localization and silencing activities of Xist have long been enigmatic, but genomics, proteomics, super-resolution microscopy, and innovative genetic approaches have produced significant new insights in recent years. In this review, I summarize and integrate these findings with a particular focus on the redundant yet mutually reinforcing pathways that enable long-term transcriptional repression throughout the soma. This includes an exploration of concurrent epigenetic changes acting in parallel within two distinct compartments of the inactive X. I also examine how Polycomb repressive complexes 1 and 2 and macroH2A may bridge XCI establishment and maintenance. XCI is a remarkable phenomenon that operates across multiple scales, combining changes in nuclear architecture, chromosome topology, chromatin compaction, and nucleosome/nucleotide-level epigenetic cues. Learning how these pathways act in concert likely holds the answer to the riddle posed by Cattanach’s and other autosomal translocations: What makes the X especially receptive to XCI?