Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases
Camille M. Syrett, … , Michael Atchison, Montserrat C. Anguera
Camille M. Syrett, … , Michael Atchison, Montserrat C. Anguera
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e126751. https://doi.org/10.1172/jci.insight.126751.
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Research Article Cell biology

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

Abstract

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.

Authors

Camille M. Syrett, Bam Paneru, Donavon Sandoval-Heglund, Jianle Wang, Sarmistha Banerjee, Vishal Sindhava, Edward M. Behrens, Michael Atchison, Montserrat C. Anguera

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Figure 1

Xist RNA and heterochromatin marks disappear from the Xi during T cell development.

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Xist RNA and heterochromatin marks disappear from the Xi during T cell d...
(A) Schematic of thymocyte differentiation in BM and thymus, as well as mature T cell subsets in the spleen. (B) Representative Xist RNA FISH images of nuclei from each thymocyte subset. (C) Quantification of Xist RNA localization patterns from each stage of thymocyte development. Results from 4 different female mice (mice A–D) are shown. Numbers above each column indicate number of nuclei counted. Statistical significance for each type of Xist RNA localization pattern across DN1-DP was determined using 1-way ANOVA; there was no statistically significant difference across all groups. (D) Sequential Xist RNA FISH and IF for H3K27me3 for DN1–4 (DP thymocytes shown in Supplemental Figure 2). White arrows denote H3K27me3 foci. (E) Quantification of colocalization patterns for Xist RNA and H3K27me3 at the Xi. Colocalization of Xist RNA and H3K27me3 focus (blue bars), Xist RNA signals alone (orange), nuclei without either signals (purple), or H3K27me3 focus (green). Numbers above each column indicate number of nuclei counted. Results from 2 different mice (mice E and F) are shown. Statistical significance for each type of Xist RNA/H3K27me3 colocalization pattern across DN1–4 was determined using 1-way ANOVA; there was no statistically significant difference across all groups. (F) Sequential Xist RNA FISH and H3K27me3 in mature thymic CD4+ and CD8+ T cells. (G) Quantification of Xist RNA localization patterns for thymic CD4+ and CD8+ T cells (left). Results from 2 different mice (labeled 1 and 2) are shown. Quantification of colocalization patterns for Xist RNA and H3K27me3 in mature thymic T cells from 1 female mouse (right). Numbers above each column indicate number of nuclei counted. Statistical significance for each type of Xist RNA localization pattern was determined using 1-way ANOVA; there was no statistically significant difference across all groups.