Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X

Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):E2029-38. doi: 10.1073/pnas.1520113113. Epub 2016 Mar 21.


Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.

Keywords: X chromosome inactivation; XIST RNA; epigenetics; female-biased autoimmunity.

Publication types

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

MeSH terms

  • Animals
  • Female
  • Humans
  • Immunity / genetics
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Lymphocyte Activation
  • Lymphocytes / metabolism*
  • Male
  • Mice
  • RNA, Long Noncoding / genetics
  • RNA, Messenger / genetics
  • X Chromosome Inactivation*


  • RNA, Long Noncoding
  • RNA, Messenger
  • XIST non-coding RNA