Inactive X chromosome (Xi)

The inactive X chromosome (Xi) is one of the two X chromosomes in female mammalian cells that undergoes epigenetic silencing through X chromosome inactivation (XCI) to achieve dosage compensation of X-linked genes with males, who have a single active X chromosome. This process is initiated early in embryonic development when the long non-coding RNA Xist coats the chosen X chromosome in cis, recruiting silencing complexes like PRC1 and PRC2 to induce heterochromatin formation, chromatin compaction into a Barr body, and suppression of most gene expression. Despite silencing, about 25% of Xi genes escape inactivation, particularly those with Y homologs, and recent findings reveal Xi's active role in modulating gene expression on the paired active X (Xa) chromosome, influencing overall dosage through trans-regulation. Xi adopts a unique bipartite 3D structure near the nuclear periphery, maintained by lncRNAs like Xist, Dxz4, and Firre, which control chromatin modifications such as H3K27me3 enrichment and TAD attenuation. Dysregulation of Xi maintenance, as seen in Xist deletions, can lead to partial reactivation of silenced genes. In disease contexts, Xi reactivation is explored therapeutically for X-linked conditions like Rett syndrome (MECP2 mutations), where shifting inactivation or unsilencing the wild-type allele on Xi could restore function, though challenges include precise control to avoid dosage imbalances contributing to sex-biased phenotypes in cancer, neurodegeneration, and immunity.

Other names

inactive XXiBarr body