An Excess of XIST
Montserrat Anguera, PhD, associate professor of biomedical sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, says the study has helped unify several poorly understood observations in the field. “I really, really liked this paper,” says Dr. Anguera, who studies how X inactivation helps maintain the immune system but wasn’t involved with the new research.
On its own, the increased expression of XIST in the lymphocytes of patients with lupus may not seem especially noteworthy, she says. But the study helped clarify a functional reason for why that excess matters, “and that’s what we, in my lab, found so exciting about this study.”
Although XIST is normally associated with X inactivation via physical binding to one X chromosome, it and certain other transcripts can partially escape that inactivation. In T cells and B cells from patients with lupus, Dr. Anguera and colleagues have shown that the mechanism tethering XIST RNA to the X chromosome is impaired, leading to further escape.
“Not only are these cells transcribing more XIST, but they’re not able to keep the RNA locked down onto the chromosome,” she says. “So when you have a cell exploding and you have the release of the debris, you’re more likely to have these free RNA ligands able to bind to and then serve as a source for TLR7 activation.” What, specifically, is driving the tethering defect is unclear, but Dr. Anguera’s work suggests a clear association with lupus activity that can, in effect, increase TLR7 activation.
Dr. Anguera says the research also provides a new opening for investigating the relatively unexplored potential of hormone-mediated regulation on the X chromosome to help different regions escape silencing and spur the development of autoimmune diseases, such as lupus. “I get really excited thinking about how these two areas are going to come and interact,” she says.
The immunological phenomena, Dr. Antiochos notes, could be relevant for multiple diseases with a clear female bias, like Sjögren’s disease. For SLE, he says, higher levels of XIST RNA may help stratify the risk of disease development or future flares among women, although testing that potential will require longitudinal studies. The findings have raised the additional possibility of targeting the TLR7-XIST interaction as a therapeutic strategy. Because patients with SLE who have upregulated XIST would be expected to be more prone to exaggerated signaling through that pathway, Dr. Antiochos says, they may benefit from TLR7 inhibitors as well.
