Xist ribonucleoproteins promote female sex-biased autoimmunity

Cell. 2024 Feb 1;187(3):733-749.e16. doi: 10.1016/j.cell.2023.12.037.

Authors

Diana R Dou¹, Yanding Zhao¹, Julia A Belk¹, Yang Zhao¹, Kerriann M Casey², Derek C Chen¹, Rui Li¹, Bingfei Yu¹, Suhas Srinivasan¹, Brian T Abe¹, Katerina Kraft¹, Ceke Hellström³, Ronald Sjöberg³, Sarah Chang⁴, Allan Feng⁴, Daniel W Goldman⁵, Ami A Shah⁵, Michelle Petri⁵, Lorinda S Chung⁴, David F Fiorentino⁶, Emma K Lundberg⁷, Anton Wutz⁸, Paul J Utz⁹, Howard Y Chang¹⁰

Affiliations

¹ Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
³ Autoimmunity and Serology Profiling, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
⁴ Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA.
⁷ School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden; Departments of Bioengineering and Pathology, Stanford University, Stanford, CA, USA.
⁸ Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland.
⁹ Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: howchang@stanford.edu.

PMID: 38306984
PMCID: PMC10949934 (available on 2025-02-01)
DOI: 10.1016/j.cell.2023.12.037

Abstract

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.

Keywords: RNA binding protein; XIST; autoantibody; autoimmunity; long non-coding RNA.

MeSH terms

Animals
Autoantibodies* / genetics
Autoimmune Diseases* / genetics
Autoimmunity / genetics
Female
Humans
Male
Mice
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism
Sex Characteristics
X Chromosome / genetics
X Chromosome / metabolism
X Chromosome Inactivation

Substances

Autoantibodies
Ribonucleoproteins
RNA, Long Noncoding
XIST non-coding RNA

Abstract

MeSH terms

Substances

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