Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases

• DOI: 10.1172/jci.insight.126751
• Publication Date: 2019-04-03T17:41:59Z
• Authors: Camille M. Syrett; Bam Paneru; Donavon Sandoval-...; Jianle Wang; Sarmistha Banerjee; Vishal Sindhava; Edward M. Behrens; Michael Atchison; Montserrat C. Ang...
• Keywords: Male; T-Lymphocytes; Datasets as Topic; Autoimmunity; Lymphocyte Activation; 3. Good health; Histones; Disease Models, Animal; Mice; Sex Factors; T-Lymphocyte Subsets; Heterochromatin; Animals; Humans; Lupus Erythematosus, Systemic; Female; RNA, Long Noncoding; RNA-Seq; Single-Cell Analysis; Child; Spleen

Systemic lupus erythematosus (SLE) is an autoimmune disorder that predominantly affects women and is driven by autoreactive T cell-mediated inflammation. It is known that individuals with multiple X-chromosomes are at increased risk for developing SLE; however, the mechanisms underlying this genetic basis are unclear. Here, we use single cell imaging to determine the epigenetic features of the inactive X (Xi) in developing thymocytes, mature T cell subsets, and T cells from SLE patients and mice. We show that Xist RNA and heterochromatin modifications transiently reappear at the Xi and are missing in mature single positive T cells. Activation of mature T cells restores Xist RNA and heterochromatin marks simultaneously back to the Xi. Notably, X-chromosome inactivation (XCI) maintenance is altered in T cells of SLE patients and late-stage-disease NZB/W F1 female mice, and we show that X-linked genes are abnormally upregulated in SLE patient T cells. SLE T cells also have altered expression of XIST RNA interactome genes, accounting for perturbations of Xi epigenetic features. Thus, abnormal XCI maintenance is a feature of SLE disease, and we propose that Xist RNA localization at the Xi could be an important factor for maintaining dosage compensation of X-linked genes in T cells.