Xist ribonucleoproteins promote female sex-biased autoimmunity

• Published in: Cell 2024-02, Vol.187 (3), p.733-749.e16
• Main Authors: Dou, Diana R., Zhao, Yanding, Belk, Julia A., Zhao, Yang, Casey, Kerriann M., Chen, Derek C., Li, Rui, Yu, Bingfei, Srinivasan, Suhas, Abe, Brian T., Kraft, Katerina, Hellström, Ceke, Sjöberg, Ronald, Chang, Sarah, Feng, Allan, Goldman, Daniel W., Shah, Ami A., Petri, Michelle, Chung, Lorinda S., Fiorentino, David F., Lundberg, Emma K., Wutz, Anton, Utz, Paul J., Chang, Howard Y.
• Format: Article
• Language: English
• Subjects: Animals; autoantibodies; Autoantibodies - genetics; autoantibody; Autoimmune Diseases - genetics; autoimmunity; Autoimmunity - genetics; B-lymphocytes; chromatin; chromosome number; Female; females; gene dosage; gene expression; genetically modified organisms; Humans; long non-coding RNA; Male; males; Mice; non-coding RNA; ribonucleoproteins; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA binding protein; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Sex Characteristics; sex chromosomes; X Chromosome - genetics; X Chromosome - metabolism; X Chromosome Inactivation; XIST
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.12.037

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding 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 comprising 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 multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations 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. [Display omitted] •Transgenic mouse models inducibly express Xist in male animals•Xist expression in males induces autoantibodies and autoimmune pathology•Xist in males reprograms T and B cell populations to female-like patterns•Autoantibodies to Xist RNP characterize female-biased autoimmune diseases in patients The Xist RNA protein complex, present only in females, is immunogenic and may underlie female-biased autoimmunity.