Sjögren's syndrome X‐chromosome dose effect: An epigenetic perspective

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting exocrine glands leading to mouth and eyes dryness. The extent to which epigenetic DNA methylation changes are responsible for an X-chromosome dose effect has yet to be determined. Our objectives were to (i) describe how epigenetic DNA methylation changes could explain an X-chromosome dose effect in SS for women with normal 46,XX genotype and (ii) determine the relevant relationships to this dose effect, between X-linked genes, genes controlling X-chromosome inactivation (XCI) and genes encoding associated transcription factors, all of which are differentially expressed and/or differentially methylated in the salivary glands of patients with SS. We identified 58 upregulated X-chromosome genes, including 22 genes previously shown to escape XCI, based on the analysis of SS patient salivary gland GEO2R gene expression datasets. Moreover, we found XIST and its cis regulators RLIM, FTX, and CHIC1, and polycomb repressor genes of the PRC1/2 complexes to be upregulated. Many of the X-chromosome genes implicated in SS pathogenesis can be regulated by transcription factors which we found to be overexpressed and/or differentially methylated in patients with SS. Determination of the mechanisms underlying methylation-dependent gene expression and impaired XCI is needed to further elucidate the etiopathogenesis of SS.

Salivary‐gland‐protective regulatory T‐cell dysfunction underlies female‐specific sialadenitis in the non‐obese diabetic mouse model of Sjögren syndrome

“…Along these lines, recent studies in humans found increased frequency of an extra X chromosome in males and females with Sjögren syndrome supporting the role of X chromosome genes in increasing risk of autoimmunity. Similarly, epigenetic DNA methylation changes may contribute to an increased dose effect by allowing access to genes on the inactivated X chromosome in females with normal karyotypes …”

Three hematologic/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis

“…Therefore, we propose that NEAT1-miR-212-3p/miR-132-3p/miR-129-5p-TTK might be a potential RNA regulatory pathway to regulate the disease progression of early RA. Additionally, although lncRNA XIST has not been reported in RA, it has been reported to be upregulated in another autoimmune disease, Sjogren's syndrome [31]. We hypothesize that XIST-miR-25-3p/miR-129-5p-GZMA has an important regulatory role in RA.…”

Expression of ETS1 and LEF1 in salivary glands of Sjögren syndrome patients

“…Indeed, expression of MMP9 promotes lymphocytic infiltration in the SG tissue (Perez et al, ). Meanwhile, increased MMP9 expression in SGECs is a pathogenic hallmark of pSS, resulting as a consequence of the action of etiological factors, for example, X chromosome dose effect and interactions with lymphocytes impairing the PKC‐gamma/ERK/DNMT1 pathway in SGECs (Mougeot, Noll, & Bahrani Mougeot, ; Renaudineau & Ballestar, ).…”