B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells

Cell. 2021 Apr 1;184(7):1790-1803.e17. doi: 10.1016/j.cell.2021.02.015. Epub 2021 Mar 17.


The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.

Keywords: RNA binding protein; X chromosome inactivation; chromatin; epigenetic memory; long non-coding RNA; sex-biased immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology*
  • COVID-19* / genetics
  • COVID-19* / immunology
  • Cell Line
  • DNA Methylation
  • Female
  • Gene Silencing
  • Humans
  • Lupus Erythematosus, Systemic* / genetics
  • Lupus Erythematosus, Systemic* / immunology
  • RNA, Long Noncoding / physiology*
  • Toll-Like Receptor 7 / immunology*
  • X Chromosome Inactivation*


  • RNA, Long Noncoding
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • XIST non-coding RNA