Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unk...

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Bibliographic Details
Published in:	Nature communications 2019-05, Vol.10 (1), p.2164-2164, Article 2164
Main Authors:	Odhams, Christopher A, Roberts, Amy L, Vester, Susan K, Duarte, Carolina S T, Beales, Charlie T, Clarke, Alexander J, Lindinger, Sonja, Daffern, Samuel J, Zito, Antonino, Chen, Lingyan, Jones, Leonardo L, Boteva, Lora, Morris, David L, Small, Kerrin S, Fernando, Michelle M A, Cunninghame Graham, Deborah S, Vyse, Timothy J
Format:	Article
Language:	eng
Subjects:	3' Untranslated regions 3' Untranslated Regions - genetics Adult Age Factors Autoimmune diseases Case-Control Studies Chromatin Chromosomes, Human, X - genetics Chronic conditions Deactivation Female Females Gene expression Gene mapping Genes, X-Linked - genetics Genes, X-Linked - immunology Genetic Predisposition to Disease Humans Immunology Inactivation Interferon Interferon Type I - immunology Interferon Type I - metabolism Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Lupus Lupus Erythematosus, Systemic - genetics Lupus Erythematosus, Systemic - immunology Male Mapping Pathogenesis Promoter Regions, Genetic - genetics Sex Sex Factors Sexual dimorphism Systemic lupus erythematosus TLR7 protein Toll-Like Receptor 7 - genetics Toll-like receptors X-chromosome inactivation
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Summary:	Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.
ISSN:	2041-1723 2041-1723