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

Abstract

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.

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

“…CXorf21 is located at gene locus Xp21.2 and escapes X-inactivation ( 68 , 69 ). It is implicated in SLE, which predominantly affects women and KS males, and is expressed at higher rates in individuals with SLE ( 69 ).…”

“…CXorf21 is located at gene locus Xp21.2 and escapes X-inactivation ( 68 , 69 ). It is implicated in SLE, which predominantly affects women and KS males, and is expressed at higher rates in individuals with SLE ( 69 ). Lipopolysaccharide, IFN-γ, and IFN-α have been observed to increase CXorf21 expression in monocytes and B cells, suggesting possible roles in both innate and adaptive immunity ( 68 ).…”

Type I IFN-dependent antibody response at the basis of sex dimorphism in the outcome of COVID-19

“…TLR7 and IRAK1 are critical to IFN-α-mediated antiviral immune responses and antibody-mediated immunosurveillance against endogenous retroviruses reactivation [ 35 ]. CXorf21, a protein co-localizing with endosomal resident TLR7, is a binding partner of the SLE-associated gene SLC15A4 in the regulation of endosomal pH [ 36 , 37 ], and is particularly active in pDCs, representing the main source of IFN-α in the immune system [ 38 ]. Sex-based differences in the innate function of human pDCs have been reported.…”

Species-Specificity of Transcriptional Regulation and the Response to Lipopolysaccharide in Mammalian Macrophages

“…Although the 83 amino acid Orf is conserved across species, this is also the host gene for miR-147, a microRNA induced by LPS in mouse macrophages and implicated in feedback regulation (Liu et al, 2009). CXorf21, expressed and further inducible by LPS in all the large animals, as in humans (Baillie et al, 2017), contains risk alleles for systemic lupus erythematosus and Sjögren's syndrome (Harris et al, 2019;Odhams et al, 2019). Although not in the pseudoautosomal region, the gene escapes X inactivation and is proposed to underly increased female autoimmune disease prevalence in humans.…”