DNA methylation similarities in genes of black South Africans with systemic lupus erythematosus and systemic sclerosis

Abstract

BackgroundSystemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are systemic autoimmune connective tissue diseases that share overlapping clinico-pathological features. It is highly probable that there is an overlap in epigenetic landscapes of both diseases. This study aimed to identify similarities in DNA methylation changes in genes involved in SLE and SSc. Global DNA methylation and twelve genes selected on the basis of their involvement in inflammation, autoimmunity and/or fibrosis were analyzed using PCR arrays in three groups, each of 30 Black South Africans with SLE and SSc, plus 40 healthy control subjects.ResultsGlobal methylation in both diseases was significantly lower (<25 %) than in healthy subjects (>30 %, p = 0.0000001). In comparison to healthy controls, a similar gene-specific methylation pattern was observed in both SLE and SSc. Three genes, namely; PRF1, ITGAL and FOXP3 were consistently hypermethylated while CDKN2A and CD70 were hypomethylated in both diseases. The other genes (SOCS1, CTGF, THY1, CXCR4, MT1-G, FLI1, and DNMT1) were generally hypomethylated in SLE whereas they were neither hyper- nor hypo-methylated in SSc.ConclusionsSSc and SLE patients have a higher global hypomethylation than healthy subjects with specific genes being hypomethylated and others hypermethylated. The majority of genes studied were hypomethylated in SLE compared to SSc. In addition to the commonly known hypomethylated genes in SLE and SSc, there are other hypomethylated genes (such as MT-1G and THY-1) that have not previously been investigated in SLE and SSc though are known to be hypermethylated in cancer.

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

“…Altorok et al performed a genome-wide DNA methylation analysis in SSc patients with diffuse or limited disease, as well as age-, sex-, and ethnicity- matched healthy controls using the Illumina Infinium Human Methylation 450 BeadChip array, which covers over 485,000 CpG sites in the entire genome [97]. A total of 2710 and 1021 differentially methylated CpG sites were identified in diffuse SSc and limited SSc, respectively, with a large proportion of them being hypomethylated (61% in diffuse and 90% in limited), agreeing with previous studies that showed global hypomethylation in various cell types, including fibroblasts, in SSc [79, 85, 98]. This unbiased approach identified genes that were affected by DNA methylation in SSc including ones that encode collagen, ECM, transcription factors, as well as genes that are involved in the TGFβ pathway and Wnt pathway (listed in Table 3), echoing and expanding the results from hypothesis-driven studies mentioned earlier.…”

“…They reported that Th17-specific transcription factors, RORC1 and 2, were hypermethylated in PBMCs. The DNA methylation results obtained from whole blood [85] was similar to what was published in CD4+ T cells: FOXP3 and CD70 were hypomethylated, however CD11a was hypermethylated instead, pointing to the importance of examining epigenetic changes in individual cell types. These studies suggest an epigenetic impact on immune dysregulation in SSc.…”

Integration of Genome-Wide DNA Methylation and Transcription Uncovered Aberrant Methylation-Regulated Genes and Pathways in the Peripheral Blood Mononuclear Cells of Systemic Sclerosis

“…SSc is a systemic disease and involves multiple organs, tissues, and cell types. Previous data were generated from fibroblast [ 13 , 14 ], purified CD4 + T cells [ 8 , 14 , 15 ], whole blood cells [ 16 ], and skin biopsy [ 17 ]. Peripheral blood mononuclear cells (PBMCs) represent a broad spectrum of cell types including T cells, B cells, NK cells, monocytes, and dendritic cells, which all played major roles in immunological events.…”

DNA methylation regulated gene expression in organ fibrosis

“…Hypoxia can directly methylate Thy-1 promoter region to downregulate its expression in lung fibroblasts (80). In contrast to pulmonary fibrosis, Thy-1 is found hypomethylated in black South Africans with systemic lupus erythematosus (84). …”