Sex bias in autoimmune diseases such as systemic lupus erythematosus (SLE) has been attributed to several factors, including sex hormones, sex chromosome gene dosage and microchimerism. A study published in JCI Insight provides new evidence for abnormal X-chromosome inactivation in T cells from patients with SLE, suggesting that faulty epigenetic control of gene dosage could be a factor contributing to sex bias in this disease.

Credit: Springer Nature Limited

In every cell containing two X chromosomes, one X chromosome is randomly chosen to be inactivated in a process orchestrated by the long noncoding RNA Xist, which recruits chromatin complexes that create epigenetic modifications, thereby silencing genes. “We were motivated to understand why there is such a strong female bias for some autoimmune diseases, and hypothesized that there must be a role for X-chromosome inactivation,” states corresponding author Montserrat Anguera.

The researchers first investigated patterns of Xist RNA transcripts in mouse T cells at various stages of differentiation and activation. “We used RNA fluorescence in situ hybridization (FISH) to visualize the localization patterns for the Xist RNA within the nuclei of T cells,” explains Anguera. “In resting cells, Xist RNA transcripts were missing from the inactive X, and in stimulated cells Xist RNA coated the inactive X.”

In NZB/W F1 female mice, which spontaneously develop lupus-like disease, patterns of Xist RNA transcripts in CD4+ T cells at pre-disease and early disease stages were similar to those in cells from healthy female wild-type mice. However, during late-stage disease, Xist RNA was mislocalized in NZB/W F1 female mice compared with wild-type female mice, being present in 40% of resting T cells and occurring in dispersed patterns in stimulated T cells.

Similar changes to Xist RNA patterns were seen in resting and stimulated T cells from patients with SLE compared with cells from healthy individuals, indicating that part of the X chromosome was reactivated in SLE.

“The most important finding from this work is that there are dispersed Xist RNA transcripts across the nuclei in T cells from patients with SLE, instead of robust localization at the X chromosome,” says Anguera. “This observation suggested to us that gene expression from the X chromosome might be affected, and we discovered that over a hundred X-linked genes were overexpressed in CD4+ T cells from patients with SLE.”

These X-linked genes included those known to escape X-chromosome inactivation, such as KDM5C and JPX, and important immune-regulatory genes that would normally be transcriptionally silenced, such as FOXP3 and IL2RG.

“Moving forward, we are curious to investigate whether the regulation of X-chromosome inactivation is also perturbed in B cells,” concludes Anguera.