What a ‘silenced’ chromosome can tell us about autoimmunity
Two studies led by Penn Vet’s Montserrat Anguera examine the process of X chromosome inactivation in immune cells, paving the way to a better understanding of the molecular mechanisms underlying lupus and other female-biased autoimmune diseases.
3 min. read
Key Takeaways
Lupus occurs more frequently in individuals with multiple X chromosomes, suggesting genetic involvement from the X chromosome in this autoimmune disorder.
When genes on one X chromosome are not properly “silenced” in B cells—a white blood cell that plays a central role in the immune response—this has been linked to lupus.
Penn Vet’s Montserrat Anguera and colleagues investigate the molecular mechanisms of silencing a chromosome—known as X inactivation—in B cells.
They find that B cells maintain X inactivation through pathways other than somatic cells, and that disrupting it triggers and exacerbates lupus-like disease in preclinical models.
These findings pave the way for a better understanding of the molecular mechanisms underlying female-biased immune responses.
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.
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, says Anguera. 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, says Anguera, adding that their 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 a pair of studies published in Cell Reports, Anguera and her team investigate the molecular mechanisms of X inactivation in B cells and the role for Xist RNA in this process.
In one study, they examined how X inactivation is maintained in activated and naïve 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 naïve 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, explains Anguera. Even without Xist RNA actively “patrolling” across the inactive X chromosome, the access is still restricted as 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,” says Anguera. She adds that their 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 Xistdeletion in B cells alters B cell function, especially in the context of chronic inflammation,” says Anguera. “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.
Toothacre et al. study: Other authors are Natalie E. Toothacre and Kiara L. RodrÍguez-Acevedo of Penn Vet and Keenan J. Wiggins and Christopher D. Scharer of Emory University.
This research was supported by NIH R01 AI134834 and R01 AI168047 and Lupus Research Alliance Target in Lupus grant.
Lovell et al. study: Other authors are Claudia D. Lovell, Hayley K. Amerman, and Natalie E. Toothacre of Penn Vet; Michael P. Cancro of Penn Medicine; and Nikhil Jiwrajka of Penn Vet and Penn Med.
This research was supported by NIH R01 AI134834 and R01 AI168047, Penn MSTP T32 Training Grant GM07170, Rheumatology Research Foundation Future Physician Scientist Award, the Lupus Foundation of America Goldie Simon and Gina M. Finzi Awards, the National Institutes of Health NIAID F30 AI174437, Rheumatology Research Foundation Scientist Development Award, Scleroderma Research Foundation Postdoctoral Fellowship Award, Penn I3H & Colton Center for Autoimmunity Pilot Grant, and NIH R21-AR081588-01.
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