ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
XIST expression and hypermethylation of the X chromosome in males with systemic lupus erythematosus
Helen Masson 1
Jonathan Crawford 2
David Gemperline 3
James Scherschel 3
Guilherme Rocha 3
Christoph Preuss 3
Isabella Wulur 3
Matthew Linnik 3
Richard Higgs 3
Ernst Dow 3
1. Eli Lilly (United States), Indianapolis, United States
2. Indiana Biosciences Research Institute, Indianapolis, United States
3. Eli Lilly and Company, Indianapolis, United States
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Abstract
Systemic Lupus Erythematosus (SLE) exhibits a pronounced sex bias, affecting females approximately nine times more frequently than males; however, males tend to experience a more severe clinical course yet the molecular basis for these differences remains unclear. Leveraging epigenomic, transcriptomic, and proteomic data from the whole blood of 720 SLE patients (679 females, 41 males) and 84 healthy controls (77 females, 7 males), we conducted comprehensive multi-omic analyses to identify sex-specific molecular features of this disease. The strongest signal differentiating males and females with SLE was the aberrant expression of the long non-coding RNA, XIST, in males. This XIST expression in males with SLE was bimodal, with 54% of males having elevated XIST expression, and correlated with disease severity. Males with SLE also exhibited significant hypermethylation of the X chromosome and transcriptional silencing of X-linked genes – hallmarks of X-chromosome inactivation (XCI), a process typically restricted to females. These results suggest that X-chromosome silencing by XIST may contribute to SLE disease in males.
Summary
Keywords
multi-omic, sexual dimorphism, systemic lupus erythematosus (SLE), X-chromosome Inactivation (XCI), XIST
Received
10 November 2025
Accepted
26 January 2026
Copyright
© 2026 Masson, Crawford, Gemperline, Scherschel, Rocha, Preuss, Wulur, Linnik, Higgs and Dow. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ernst Dow
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