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

PLoS Genet. 2017 Oct 9;13(10):e1007050. doi: 10.1371/journal.pgen.1007050. eCollection 2017 Oct.

Abstract

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.

MeSH terms

  • Animals
  • Epigenesis, Genetic
  • Female
  • Gene Deletion
  • Gene Silencing*
  • Genes, X-Linked
  • Heterochromatin / genetics
  • Lymphocyte Activation / genetics*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Precursor Cells, B-Lymphoid / metabolism*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / isolation & purification
  • Sequence Analysis, RNA
  • Spleen / cytology
  • Up-Regulation
  • X Chromosome / genetics
  • X Chromosome Inactivation / genetics*
  • YY1 Transcription Factor / genetics
  • YY1 Transcription Factor / metabolism*

Substances

  • Heterochromatin
  • RNA, Long Noncoding
  • XIST non-coding RNA
  • YY1 Transcription Factor
  • Yy1 protein, mouse