Open AccessAltered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases
Author(s) -
Camille M. Syrett,
Bam Paneru,
Donavon Sandoval-Heglund,
Jianle Wang,
Soumya Banerjee,
Vishal Sindhava,
Edward M. Behrens,
Michael L. Atchison,
Montserrat C. Anguera
Publication year - 2019
Publication title -
jci insight
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 4.099
H-Index - 45
ISSN - 2379-3708
DOI - 10.1172/jci.insight.126751
Subject(s) - xist , x inactivation , x chromosome , epigenetics , biology , rna , autoimmune disease , immunology , t cell , disease , dosage compensation , gene , genetics , medicine , antibody , immune system
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.