Xite, X-inactivation intergenic transcription elements that regulate the probability of choice

Abstract

Allelic expression differences contribute to phenotypic variation. In X chromosome inactivation (XCI), unfavorable XCI ratios promote X-linked disease penetrance in females. During XCI, one X is randomly silenced by Xist. X chromosome choice is determined by asymmetric expression of Tsix whose antisense action represses Xist. Here, we discover a cis element in the mouse X-inactivation center that regulates Tsix. Xite harbors intergenic transcription start sites and DNaseI hypersensitive sites with allelic differences. At the onset of XCI, deleting Xite downregulates Tsix in cis and skews XCI ratios, suggesting that Xite promotes Tsix persistence on the active X. Truncating Xite RNA is inconsequential, indicating that Xite action does not require intact transcripts. We propose that allele-specific Xite action promotes Tsix asymmetry and generates X chromosome inequality. Therefore, Xite is a candidate for the Xce, the classical modifier of XCI ratios.