Abstract
BackgroundSystemic 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.MethodsDNA samples exacted from CD4+ T cells of 48 SSc patients and 16 healthy controls were hybridized on MethylationEPIC BeadChip array. In parallel, gene expression was interrogated by hybridizing total RNA on Clariom™ S array. Downstream bioinformatics analyses were performed to identify correlating differentially methylated CpG positions (DMPs) and differentially expressed genes (DEGs), which were then confirmed utilizing previously published promoter capture Hi-C (PCHi-C) data.ResultsWe identified 9112 and 3929 DMPs and 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 PCHi-C data, we observed that 212 CD4+ T cell-specific pairs of DMP-DEG also formed part of three-dimensional promoter-enhancer networks, potentially involving CTCF. Finally, combining PCHi-C data with SSc GWAS data, we identified four important SSc-associated susceptibility loci, TNIP1 (rs3792783), GSDMB (rs9303277), IL12RB1 (rs2305743), and CSK (rs1378942), that could potentially interact with DMP-DEG pairs cg17239269-ANXA6, cg19458020-CCR7, cg10808810-JUND, and cg11062629-ULK3, respectively.ConclusionOur study unveils a potential link between genetic, epigenetic, and transcriptional deregulation in CD4+ T cells of SSc patients, providing a novel integrated view of molecular components driving SSc pathogenesis.
Highlights
Systemic 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
SSc patients can be broadly categorized into three groups based on the extent of skin involvement: those with restricted involvement affecting the limbs distal to the elbows or knees with or without face and neck involvement are classified as limited cutaneous SSc or those with proximal involvement affecting above the elbows and knees are classified as diffuse cutaneous SSc and sine scleroderma with Raynaud’s phenomenon, visceral involvement, and autoantibodies but no skin involvement [2]
DNA methylation deregulation in SSc CD4 T cells To gain insights into functional and molecular alterations of T lymphocytes in the context of SSc pathogenesis, we first isolated CD4+ T lymphocytes from the peripheral blood mononuclear cells (PBMCs) of 48 SSc patients and 16 age- and sex-matched healthy donors (HD) by CD4+ positive cell sorting (Fig. 1a, b; Additional file 1: Table S1)
Summary
Systemic 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. Genetics studies have revealed that SSc heritability is complex with the HLA loci playing an important contribution to disease risk [7]. Recent genome-wide association (GWAS) and immunochip array SNP studies revealed the presence of numerous non-HLA loci that associate with disease onset, including genes of type I interferon pathway, interleukin-12 pathway, and TNF pathway as well as B and T cell-specific genes [8,9,10,11,12,13,14]. Genetic variants do not account for all of the genetic burden of SSc, where other factors, such as epigenetic dysregulation, play an indispensable role in disease pathogenesis [5, 16]
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