Role for Abnormal Gene Expression From the Inactive X in Female-Biased Lupus Disease
Abstract
This project addresses the FY17 topic area "Understand how the underlying genetic components of lupus relate to clinical disease characteristics using functional genomic studies." Approximately 85% of lupus patients are women, and this disease predominantly affects black, Hispanic, and Asian women, who comprise 50% of enlisted women. The incidence of lupus in the military is high and continues to grow as the number of enlisted women increases. It is unknown why women are predisposed to acquire lupus, and there is strong evidence suggesting that X-chromosomes are involved. The X-chromosome is enriched for immune-related genes, and some are abnormally over-expressed in lupus patients. Notably, we discovered that the inactive X-chromosome is regulated differently in female lymphocytes and is predisposed to partial reactivation in B cells. Our findings represent a new paradigm for understanding the genetic predisposition for lupus for women. Our work, which investigates the genetic basis for predisposition for lupus, will ultimately impact all enlisted women (XX) and men with Klinefelter’s syndrome (XXY), who have more than one X-chromosome. At present, it is unknown why individuals with multiple X-chromosomes have increased risk to develop lupus, which is a debilitating disease with no cure. In the short term, we hope to confirm our hypothesis that partial X-reactivation is a feature of female-biased lupus, where increased expression of X-linked immunity genes is caused by reduced Xist RNA localization to inactive X-chromosome. As such, we anticipate that therapeutic approaches that increase Xist RNA localization to the inactive X for enhanced transcriptional repression could be developed. We have identified several Xist RNA binding proteins required for Xist RNA localization in activated lymphocytes. We also anticipate that our results will identify novel X-linked markers for lupus development, which may be used in a clinical setting for early detection. We believe that our hypothesis can be tested within the 3-year period of this study and that subsequent work on therapeutic approaches to increase Xist RNA localization, through increased expression of Xist RNA binding proteins, could begin immediately after and perhaps last 2 years. We would anticipate testing Xist RNA localization and the resulting gene expression studies using animal models, and clinical trials could begin to determine applicability in human patients. We believe that the health of military women will result in a stronger and more efficient military force with reduced burden of lupus. Our studies, in the long-term, will strengthen our military, serving the American public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810635
Entities
People
- Montserrat C Anguera
Organizations
- United States Army
- University of Pennsylvania