Diversity of Epigenetic Features of the Inactive X-Chromosome in NK Cells, Dendritic Cells, and Macrophages

Front Immunol. 2019 Jan 8:9:3087. doi: 10.3389/fimmu.2018.03087. eCollection 2018.


In females, the long non-coding RNA Xist drives X-chromosome Inactivation (XCI) to equalize X-linked gene dosage between sexes. Unlike other somatic cells, dynamic regulation of Xist RNA and heterochromatin marks on the inactive X (Xi) in female lymphocytes results in biallelic expression of some X-linked genes, including Tlr7, Cxcr3, and Cd40l, implicated in sex-biased autoimmune diseases. We now find that while Xist RNA is dispersed across the nucleus in NK cells and dendritic cells (DCs) and partially co-localizes with H3K27me3 in bone marrow-derived macrophages, it is virtually absent in plasmacytoid DCs (p-DCs). Moreover, H3K27me3 foci are present in only 10-20% of cells and we observed biallelic expression of Tlr7 in p-DCs from wildtype mice and NZB/W F1 mice. Unlike in humans, mouse p-DCs do not exhibit sex differences with interferon alpha production, and interferon signature gene expression in p-DCs is similar between males and females. Despite the absence of Xist RNA from the Xi, female p-DCs maintain dosage compensation of six immunity-related X-linked genes. Thus, immune cells use diverse mechanisms to maintain XCI which could contribute to sex-linked autoimmune diseases.

Keywords: NK cells; X-chromosome inactivation; Xist RNA; interferon alpha; long non-coding RNA; macrophages; plasmacytoid dendritic cells; sex differences.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Cell Nucleus / metabolism
  • Dendritic Cells / physiology*
  • Dosage Compensation, Genetic
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation
  • Genes, X-Linked
  • Genetic Variation*
  • Heterochromatin / metabolism
  • Killer Cells, Natural / physiology*
  • Macrophages / physiology*
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred NZB
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Spleen / cytology
  • Toll-Like Receptor 7 / metabolism
  • X Chromosome / genetics*
  • X Chromosome Inactivation / genetics*


  • Heterochromatin
  • Membrane Glycoproteins
  • RNA, Long Noncoding
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • XIST non-coding RNA