YY1 binding is a gene-intrinsic barrier to Xist-mediated gene silencing

Abstract

AbstractX chromosome inactivation (XCI) in mammals is mediated by Xist RNA which functions incisto silence genes on a single X chromosome in XX female cells, thereby equalising levels of X-linked gene expression relative to XY males. XCI progresses over a period of several days, with some X-linked genes silencing faster than others. Chromosomal location of a gene is an important determinant of silencing rate, but uncharacterised gene-intrinsic features also mediate resistance or susceptibility to silencing. In this study, we integrate time-course data of gene silencing and decreasing inactive X (Xi) chromatin accessibility in mouse embryonic stem cell lines with an inducibleXistallele (iXist-ChrX mESCs). Our analysis reveals that motifs bound by the transcription factor YY1 are associated with persistently accessible regulatory elements, including many promoters and enhancers of slow-silencing genes. We further show that YY1 is evicted relatively slowly from target sites on Xi, and that silencing of X-linked genes is increased upon YY1 degradation. Together our results indicate that YY1 acts as barrier to Xist-mediated silencing that is removed only at late stages of the XCI process.