Faulty X chromosome silencing may explain higher SLE rate in women
2 new studies investigate mechanisms underlying most common lupus type
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Disruption of a natural process called X-chromosome inactivation (XCI) in immune B-cells — occurring when one X chromosome in females is turned off during development — may directly contribute to the development of systemic lupus erythematosus (SLE), two new studies led by a veterinary professor suggest.
According to Montserrat Anguera, PhD, of the University of Pennsylvania’s School of Veterinary Medicine, these findings may help explain why SLE, the most common form of lupus, occurs much more frequently in women.
The researchers investigated the mechanisms underlying XCI and also looked at B-cells, the immune cells that produce self-reactive antibodies that drive SLE. In a university news story detailing the studies’ findings, Anguera, who was senior author on both, said the new research “demonstrated that circulating B cells from female SLE patients have features of impaired XCI maintenance.”
Altogether, the work reveals “a novel pathogenic [disease-related] mechanism that simultaneously accounts for the strong female sex bias of SLE,” Anguera said.
Both studies were published in the journal Cell Reports.
An autoimmune disease, SLE is caused when the body’s immune system mistakenly attacks healthy tissues, driving inflammation and the disease’s symptoms.
Number of X chromosomes tied to SLE risk
The condition occurs much more frequently in women than in men. While there is some evidence for the contribution of female sex hormones such as estrogen, previous studies have suggested that SLE risk increases with the number of X chromosomes a person has.
Females typically have two X chromosomes, while males only have one, along with a Y chromosome. As the X chromosome has many more genes than the Y chromosome, a process known as X chromosome inactivation shuts down one of the X chromosomes during early development so that X-linked gene activity is balanced between the two sexes.
According to Anguera, in immune cells, including B-cells, XCI regulation is particularly important because the X chromosome contains several immune-related genes.
To keep one X chromosome inactive, cells first coat it with an RNA molecule called Xist, or X-inactive specific transcript, which then recruits other molecules that keep the gene turned off. In one of the studies now published by Anguera and her collaborators, this process was found to have a unique regulatory mechanism in B-cells.
This study was titled “Xist RNA dependent and independent mechanisms regulate dynamic X chromosome inactivation in B lymphocytes,” and was published a few months ago.
The research team found that the normally inactive X chromosome in female B-cells carries a distinct set of epigenetic markers that help keep the genes switched off. Epigenetic modifications involve adding chemical marks to DNA that influence gene activity without altering the underlying code.
In naïve B cells, meaning those that have not been exposed to an antigen, two key marks — H3K27me3 and DNA methylation — remained enriched on the inactive X chromosome, even when Xist was no longer attached. Of note, NA methylation consists of adding methyl tags, or small chemical groups, to DNA.
According to the researchers, this suggests these marks act as a “memory” that preserves X-chromosome inactivation.
When B-cells were activated, the inactive X chromosome underwent extensive epigenetic remodeling. Xist RNA was essential for adding a single silencing mark, H2AK119Ub, whereas H3K27me3 accumulation occurred largely independently of Xist.
“We found that B cells use different pathways to maintain X inactivation than other somatic cells [body cells othe than sperm and egg cells],” Anguera said. She added that these results could help inform further studies on how gene regulation occurs in B-cells and autoimmune diseases.
Researchers seeking to understand female bias in SLE
In the second study, “Female mice with a Xist deletion in B cells can develop lupus-associated phenotypes,” the research team found that disrupting XCI in B-cells can directly contribute to lupus-like disease in female mice.
Female mice lacking Xist developed features resembling SLE, including production of self-reactive antibodies, abnormal B-cell activation, and kidney disease. The effects became even more pronounced when lupus-like disease was experimentally induced. The researchers also found depletion of H3K27me3 and increased activity of several immune-related genes on the X chromosome.
“Our findings suggest that the disruption of proper maintenance of XCI in the B cell compartment, a potential mechanism at play in female patients with SLE having disrupted patterns of XCI in B cells, likely contributes to female-biased disease phenotypes [presentations],” the researchers wrote.
According to Anguera, the study “indicates that an Xist deletion in B cells alters B cell function, especially in the context of chronic inflammation.”
This finding suggests a new disease-related mechanism that can also account for more women than men being affected by SLE, Anguera said.
Overall, according to the researchers in the first study, “These data highlight novel mechanisms governing X-linked gene expression in B cells and thus have critical implications for understanding molecular mechanisms underlying female-biased immune responses” as seen with SLE.
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