Preprint: X-inactivation escapee regions form chromatin compartments independently of CTCF and cohesin

A preprint posted to bioRxiv on 1 September 2026 revisits the molecular basis of X-chromosome inactivation escape, challenging a prevalent model in which the architectural proteins CTCF and cohesin are required to maintain the three-dimensional domains that allow certain genes to remain transcriptionally active on the otherwise silenced inactive X chromosome.

The researchers used acute degradation (degron) technology to rapidly deplete CTCF and the cohesin complex from cells, then assessed the chromatin architecture and transcriptional status of known escape regions. Contrary to the prevailing hypothesis, the escape domains were maintained even in the absence of CTCF and cohesin, indicating that these genomic regions constitute chromatin compartments that are stabilised by a separate mechanism not dependent on cohesin-mediated loop extrusion.

X-inactivation escape is of broad biological interest because the genes involved represent a source of sex-biased gene expression and are implicated in sex differences in disease susceptibility and in the phenotypic consequences of sex chromosome aneuploidy conditions such as Turner syndrome and Klinefelter syndrome. Understanding the structural basis of escape has implications for interpreting why these conditions display variable expressivity.

This is a preprint that has not yet been peer-reviewed. The work is primarily of interest to researchers in chromosome biology, gene regulation, and sex chromosome biology.