Differential DNA Methylation Landscape in Skin Fibroblasts from African Americans with Systemic Sclerosis

Abstract

The etiology and reasons underlying the ethnic disparities in systemic sclerosis (SSc) remain unknown. African Americans are disproportionally affected by SSc and yet are underrepresented in research. The aim of this study was to comprehensively investigate the association of DNA methylation levels with SSc in dermal fibroblasts from patients of African ancestry. Reduced representation bisulfite sequencing (RRBS) was performed on primary dermal fibroblasts from 15 SSc patients and 15 controls of African ancestry, and over 3.8 million CpG sites were tested for differential methylation patterns between cases and controls. The dermal fibroblasts from African American patients exhibited widespread reduced DNA methylation. Differentially methylated CpG sites were most enriched in introns and intergenic regions while depleted in 5′ UTR, promoters, and CpG islands. Seventeen genes and eleven promoters showed significant differential methylation, mostly in non-coding RNA genes and pseudogenes. Gene set enrichment analysis (GSEA) and gene ontology (GO) analyses revealed an enrichment of pathways related to interferon signaling and mesenchymal differentiation. The hypomethylation of DLX5 and TMEM140 was accompanied by these genes’ overexpression in patients but underexpression for lncRNA MGC12916. These data show that differential methylation occurs in dermal fibroblasts from African American patients with SSc and identifies novel coding and non-coding genes.

Embryonic heat conditioning in chicks induces transgenerational heat/immunological resilience via methylation on regulatory elements

“…We found most of the differential methylation in intergenic regions and on introns (Figure 2C,D,F,G). Although differential methylation of noncoding regions has been reported, 16–24 little is known about its biological functions. Initially, we used HOMER to determine motif enrichment in hypo‐ and hyper‐DMSs, and found motifs supporting our model and phenotype.…”

“…[13][14][15] To date, most studies have focused on probing the alterations in DNA methylation near genes and promoters, which are easier to mechanistically link to changes in gene expression. Nonetheless, there is a growing body of literature from different animal models, tissues, and cell types reporting on prevailing differential methylation in intergenic regions, introns, and other noncoding DNA regions, [16][17][18][19][20][21][22][23][24] following the contextual and environmental stimulus. These areas in the genome may harbor cis-and trans-regulatory elements of transcription, also known as enhancers.…”

Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis

“…Coit et al [ 70 ] identified a total of 105 and 144 differentially methylated sites and genes unique for either juvenile SSc (JSSc) and localized SSc including FGFR2, STAT3, NF-κB, IL-15, and NOTCH3 pathways. Baker Frost et al [ 71 ] intended to investigate the association of DNA methylation levels in dermal fibroblasts obtained from patients of African ancestry and found widespread reduced DNA methylation of DLX5 and TMEM140. Rezaei et al [ 72 ] suggested that hypomethylation of IRF7 promotor might play a role in SSc pathogenesis via promoting the IRF7 expression in PBMCs of patients with SSc.…”

Distinct genome-wide DNA methylation and gene expression signatures in classical monocytes from African American patients with systemic sclerosis

“…Variation in DNA methylation across ancestral populations is contributed to by genetic ancestry and environmental factors [ 20 ]. Despite the increased disease burden in African Americans and variation in DNA methylation across populations, only two genome-wide differential DNA methylation analyses have been conducted in peripheral blood and skin fibroblasts from SSc patients of African descent [ 21 , 22 ].…”