Xist ribonucleoproteins promote female sex-biased autoimmunity

Diana R. Dou; Yanding Zhao; Julia A. Belk; Yang Zhao; Kerriann M. Casey; Derek C. Chen; Rui Li; Bingfei Yu; Suhas Srinivasan; Brian T. Abe; Katerina Kraft; Ceke Hellström; Ronald Sjöberg; Sarah Chang; Allan Feng; Daniel W. Goldman; Ami A. Shah; Michelle Petri; Lorinda S. Chung; David F. Fiorentino; Emma K. Lundberg; Anton Wutz; Paul J. Utz; Howard Y. Chang

doi:10.1016/j.cell.2023.12.037

Xist ribonucleoproteins promote female sex-biased autoimmunity

Diana R. Dou, Yanding Zhao, Julia A. Belk, Yang Zhao, Kerriann M. Casey, Derek C. Chen, Rui Li, Bingfei Yu, Suhas Srinivasan, Brian T. Abe, Katerina Kraft, Ceke Hellström, Ronald Sjöberg, Sarah Chang, Allan Feng, Daniel W. Goldman, Ami A. Shah, Michelle Petri, Lorinda S. Chung, David F. FiorentinoEmma K. Lundberg, Anton Wutz, Paul J. Utz, Howard Y. Chang

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	733-749.e16
Journal	Cell
Volume	187
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2023.12.037
State	Published - Feb 1 2024

Keywords

RNA binding protein
XIST
autoantibody
autoimmunity
long non-coding RNA

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2023.12.037

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Dou, D. R., Zhao, Y., Belk, J. A., Zhao, Y., Casey, K. M., Chen, D. C., Li, R., Yu, B., Srinivasan, S., Abe, B. T., Kraft, K., Hellström, C., Sjöberg, R., Chang, S., Feng, A., Goldman, D. W., Shah, A. A., Petri, M., Chung, L. S., ... Chang, H. Y. (2024). Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell, 187(3), 733-749.e16. https://doi.org/10.1016/j.cell.2023.12.037

Dou, DR, Zhao, Y, Belk, JA, Zhao, Y, Casey, KM, Chen, DC, Li, R, Yu, B, Srinivasan, S, Abe, BT, Kraft, K, Hellström, C, Sjöberg, R, Chang, S, Feng, A, Goldman, DW , Shah, AA , Petri, M, Chung, LS, Fiorentino, DF, Lundberg, EK, Wutz, A, Utz, PJ & Chang, HY 2024, 'Xist ribonucleoproteins promote female sex-biased autoimmunity', Cell, vol. 187, no. 3, pp. 733-749.e16. https://doi.org/10.1016/j.cell.2023.12.037

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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 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.",

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doi = "10.1016/j.cell.2023.12.037",

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AU - Dou, Diana R.

AU - Zhao, Yanding

AU - Belk, Julia A.

AU - Zhao, Yang

AU - Casey, Kerriann M.

AU - Chen, Derek C.

AU - Li, Rui

AU - Yu, Bingfei

AU - Srinivasan, Suhas

AU - Abe, Brian T.

AU - Kraft, Katerina

AU - Hellström, Ceke

AU - Sjöberg, Ronald

AU - Chang, Sarah

AU - Feng, Allan

AU - Goldman, Daniel W.

AU - Shah, Ami A.

AU - Petri, Michelle

AU - Chung, Lorinda S.

AU - Fiorentino, David F.

AU - Lundberg, Emma K.

AU - Wutz, Anton

AU - Utz, Paul J.

AU - Chang, Howard Y.

PY - 2024/2/1

Y1 - 2024/2/1

N2 - 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.

AB - 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.

KW - RNA binding protein

KW - XIST

KW - autoantibody

KW - autoimmunity

KW - long non-coding RNA

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JF - Cell

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ER -

Xist ribonucleoproteins promote female sex-biased autoimmunity

Abstract

Keywords

ASJC Scopus subject areas

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