Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells.

• Main Authors: Camille M Syrett, Vishal Sindhava, Suchita Hodawadekar, Arpita Myles, Guanxiang Liang, Yue Zhang, Satabdi Nandi, Michael Cancro, Michael Atchison, Montserrat C Anguera
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2017-10-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC5648283?pdf=render
• ISSN: 1553-7390; 1553-7404

X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. Activation of mature B cells restores Xist RNA and heterochromatin to the Xi in a dynamic two-step process that differs in timing and pattern, depending on the method of B cell stimulation. Finally, we find that DNA binding domain of YY1 is necessary for XCI in activated B cells, as ex-vivo YY1 deletion results in loss of Xi heterochromatin marks and up-regulation of X-linked genes. Ectopic expression of the YY1 zinc finger domain is sufficient to restore Xist RNA localization during B cell activation. Together, our results indicate that Xist RNA localization is critical for maintaining XCI in female lymphocytes, and that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X-linked immunity genes to reactivation.