XIST ribonucleoproteins promote female sex-biased autoimmunity

Dou, D. R.; Zhao, Y.; Belk, J. A.; Casey, K. M.; Chen, D. C.; Li, R.; Yu, B.; Abe, B. T.; Kraft, K.; Hellstrom, C.; Sjoberg, R.; Chang, S. E.; Feng, A.; Goldman, D. W.; Shah, A. A.; Petri, M.; Wigley, F. M.; Chung, L. S.; Fiorentino, D. F.; Lundberg, E. K.; Wutz, A.; Utz, P. J.; Chang, H.

doi:10.1101/2022.11.05.515306

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bioRxiv · 10.1101/2022.11.05.515306

XIST ribonucleoproteins promote female sex-biased autoimmunity

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Abstract

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long noncoding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex, comprised of numerous autoantigenic components, is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multiorgan pathology in pristane-induced model of lupus than wild-type males. Xist expression in males reprogrammed T and B cell population and chromatin states to more resemble wild type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity. HIGHLIGHTSO_LITransgenic mouse models inducibly express Xist in male animals. C_LIO_LIXist expression in males induce autoantibodies and autoimmune pathology. C_LIO_LIXist in males reprograms T and B cell populations to female-like patterns. C_LIO_LIAutoantibodies to Xist RNP characterize female-biased autoimmune diseases. C_LI

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Dou, D. R., Zhao, Y., Belk, J. A., Casey, K. M., Chen, D. C., Li, R., Yu, B., Abe, B. T., Kraft, K., Hellstrom, C., Sjoberg, R., Chang, S. E., Feng, A., Goldman, D. W., Shah, A. A., Petri, M., Wigley, F. M., Chung, L. S., Fiorentino, D. F., Lundberg, E. K., Wutz, A., Utz, P. J., Chang, H.. 2022-11-05. XIST ribonucleoproteins promote female sex-biased autoimmunity. https://doi.org/10.1101/2022.11.05.515306

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