Cell 153, 1537–1551 (2013)

Credit: JEANNIE LEE

X-chromosome inactivation (XCI) leads to the transcriptional silencing of one X chromosome, thereby balancing the dosage of X-linked genes between XX females and XY males. The process is coordinated by the X-inactivation center, which includes four genes that encode long noncoding RNAs: Xist, Tsix, Xite and Jpx. The chromosome selected for inactivation transcribes Xist RNA, which localizes on that chromosome as an 'Xist cloud' and marks it for silencing. Previous studies had shown that Xist expression is positively regulated by Jpx, but how this was linked to initiation of XCI remained unclear. Sun et al. show that XCI is initiated when Jpx RNA titrates away a repressor protein from the Xist promoter, thereby activating Xist RNA expression. CTCF, an autosomal protein with known binding sites in the Xist promoter, was shown to repress Xist transcription, and CTCF-mediated repression could be relieved by enhanced Jpx RNA expression. Jpx RNA specifically binds CTCF in vitro, and UV crosslinked RNA immunoprecipitation analysis confirmed the binding interaction within cells. Gene reporter assays in cells further established that overexpression of CTCF repressed Xist expression mediated by the P2 promoter element, whereas overexpression of Jpx enhanced Xist transcription. The resulting mechanism, in which the autosomal CTCF repressor is regulated by the X-linked Jpx RNA, provides a molecular framework for sensing the 'X-to-autosome' ratios in cells, a concept that underpins current genetic models of XCI.