Epigenomics and Transcriptomics of Systemic Sclerosis CD4+ T cells reveal Long Range Dysregulation of Key Inflammatory Pathways mediated by disease-associated Susceptibility Loci

Abstract

ABSTRACTSystem sclerosis (SSc) is a genetically complex autoimmune disease mediated by the interplay between genetic and epigenetic factors in a multitude of immune cells, with CD4+ T lymphocytes as one of the principle drivers of pathogenesis. In this study, we obtained DNA methylation and expression profiles of CD4+ T cells from 48 SSc patients and 16 healthy controls. Consequently, we identified 9112 and 3929 differentially methylated CpGs positions (DMPs) and differentially expressed genes (DEGs) respectively. These DMPs and DEGs are enriched in functional categories related to inflammation and T cell biology. Furthermore, correlation analysis identified 17,500 possible DMP-DEG interaction pairs within a window of 5 Mb, and utilizing promoter capture Hi-C data, we confirmed that 212 CD4+ T cel specific pairs of DMP-DEG physically interact involving CTCF. Finally, utilizing SSc GWAS data, we identified four important SSc-associated susceptibility loci, TNIP1 (rs3792783), GSDMB (rs9303277), IL12RB1 (rs2305743) and CSK (rs1378942), that physically interact with DMP-DEG pairs cg17239269-ANXA6, cg19458020-CCR7, cg10808810-JUND and cg11062629-ULK3 respectively. Overall, our study reveals a solid link between genetic, epigenetic and transcriptional deregulation in CD4+ T cells of SSc patients, providing a novel integrated view of SSc pathogenic determinants.