What a 'silenced' chromosome can tell us about autoimmunity

by Deborah Stull, University of Pennsylvania

edited by Lisa Lock, reviewed by Robert Egan

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Systemic lupus erythematosus (SLE), the most common form of lupus, is an autoimmune disorder that occurs more frequently in women. Having multiple X chromosomes has been associated with an increased risk of developing lupus; however, the reason for this link is still not fully understood and may involve how X chromosomes are regulated in female immune cells.

Now, two studies led by Montserrat Anguera of the School of Veterinary Medicine, both published in Cell Reports, provide insight into these mechanisms, offering a better understanding of the disease.

Impaired X chromosome inactivation in B cells has been linked to lupus

Typically, in humans and most other mammals, individuals with two X chromosomes (XX) develop as female, while those with one X and one Y chromosome (XY) develop as male. Because X chromosomes contain many more genes than Y chromosomes, one of the two X chromosomes in XX individuals is randomly turned off early in development in a process called X chromosome inactivation, or XCI.

Most cells keep one X chromosome turned off by "coating" it with Xist RNA, which recruits molecular tags and packaging signals that condense and silence the X chromosome. But some genes escape this process, and X inactivation is not identical in every cell. It is also not a permanent "set it and forget it" event—cells must actively maintain the inactive state over time.

In immune cells such as B cells, how X inactivation is regulated is particularly important, Anguera says. The X chromosome carries a disproportionate number of immune-related genes and, when one immune receptor called TLR7 is overexpressed, she adds, it can lead to the development of lupus.

In both experimental models of SLE and female patients with SLE, B cells exhibit mislocalization of Xist RNA and aberrant expression of these genes, Anguera says, adding that her work "demonstrated that circulating B cells from female SLE patients have features of impaired XCI maintenance."

In chronic inflammation, she says, the mechanisms silencing one X chromosome might erode over time, contributing to the development of autoimmune disease.

B cells maintain X inactivation through different pathways, and disrupting XCI in these cells triggers and exacerbates lupus-like disease

In the studies published in Cell Reports, Anguera and her team investigate the molecular mechanisms of X inactivation in B cells and the role of Xist RNA in this process.

In one study, they examined how X inactivation is maintained in activated and naive B cells, or those that have not been exposed to an antigen. The team tested whether the patterns of silencing tags and signals depend on Xist RNA. They found that in naive B cells, the inactive X chromosome lacked some of the usual silencing features but retained others that help maintain a memory of gene silencing during early development.

The inactive X chromosome is like a building shut down by a security guard, Xist RNA, Anguera explains. Even without Xist RNA actively patrolling across the inactive X chromosome, access is still restricted because certain chemical locks remain in place.

But when the researchers activated the cells, they found that other common marks of X inactivation were restored, although via different mechanisms—some dependent on Xist and others not.

"We found that B cells use different pathways to maintain X inactivation than other somatic cells," Anguera says. She adds that the results could help inform future studies on gene regulation in B cells and its role in autoimmune disease.

In the second study, Anguera and her colleagues show that disrupting the maintenance of X inactivation in B cells by deleting Xist triggers and exacerbates lupus-like disease in preclinical models.

"Our study indicates that an Xist deletion in B cells alters B cell function, especially in the context of chronic inflammation," Anguera says. "It provides a novel pathogenic mechanism that simultaneously accounts for the strong female sex bias of SLE."

Next steps, she says, include investigating other female-biased autoimmune diseases to see whether they also exhibit impaired features of XCI maintenance. She and her team also plan to test whether Xist RNA plays a role in additional immune cell types.

Publication details

Natalie E. Toothacre et al, Xist RNA dependent and independent mechanisms regulate dynamic X chromosome inactivation in B lymphocytes, Cell Reports (2026). DOI: 10.1016/j.celrep.2026.117254

Claudia D. Lovell et al, Female mice with a Xist deletion in B cells can develop lupus-associated phenotypes, Cell Reports (2026). DOI: 10.1016/j.celrep.2026.117517

Journal information: Cell Reports

Key medical concepts

Systemic lupus erythematosusX Chromosome InactivationXIST GeneB-LymphocytesTLR7 protein, human

Clinical categories

Allergy and immunologyClinical genetics Provided by University of Pennsylvania Who's behind this story?

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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