Dataset Information

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.

SUBMITTER: Baker Frost D

PROVIDER: S-EPMC7909410 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Baker Frost DeAnna D da Silveira Willian W Hazard E Starr ES Atanelishvili Ilia I Wilson Robert C RC Flume Jonathan J Day Kayleigh L KL Oates James C JC Bogatkevich Galina S GS Feghali-Bostwick Carol C Hardiman Gary G Ramos Paula S PS

Genes 20210120 2

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 ...[more]

PMID: 33498390

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Project description:Background. The etiology and reasons underlying the ethnic disparities in systemic sclerosis (SSc) remain unknown. African-Americans (AA) are disproportionally affected by SSc, yet dramatically underrepresented in research. The role of DNA methylation in disease risk remains unclear. This analysis was conducted to comprehensive identify differentially methylated loci associated with SSc in AA. Methods. Genomic DNA was isolated from cultured dermal fibroblasts isolated from 15 AA SSc cases and 15 AA controls. All patients met the 2013 ACR/EULAR classification criteria for SSc, most (93%) presenting with diffuse cutaneous SSc. DNA methylation patterns were profiled through reduced representation bisulfite sequencing (RRBS). Alignment and methylation calling were performed using Bismarck v0.16.3 and the GRCh37/hg19 reference genome. Data was filtered, normalized, and analyzed with RnBeads v1.6.1. Differential methylation analysis was conducted on CpG, promoter, gene and system level. Results. We generated DNA methylation data for over 5 million CpGs in each sample and between 10x to 40x coverage in CpGs sites. Using the Combined Score approach implemented in RnBeads, a total of 9 CpG islands, 17 genes and 11 promoters showed significant differential methylation levels between cases and controls at the gene-level. The top differentially methylated genes constitute mostly non-coding RNA genes (42%), followed by pseudogenes (27%), then protein coding genes (19%). Enrichment analysis revealed that both hypo- and hypermethylated genes and their promoter regions were enriched for cell differentiation and immune-related gene ontology terms (hypermethylated regions: mesenchymal cell transition and differentiation; hypomethylated regions: type I IFN signaling). Conclusion. The observed DNA methylation differences between cases and controls support a modest role for DNA methylation differences in mediating susceptibility to SSc in AA. Instead of protein-coding, most differentially methylated genes comprise non-coding RNA genes, supporting a larger contribution of dysregulated regulatory elements to disease. While previous DNA methylation profiling analyses in European-Americans reported an enrichment of extracellular matrix and focal adhesion genes, our data supports a potentially stronger immune-driven etiology in AA.

Project description:Chronic obstructive pulmonary disease (COPD) is the third-leading cause of death worldwide. Identifying COPD-associated DNA methylation marks in African-Americans may contribute to our understanding of racial disparities in COPD susceptibility. We determined differentially methylated genes and co-methylation network modules associated with COPD in African-Americans recruited during exacerbations of COPD and smoking controls from the Pennsylvania Study of Chronic Obstructive Pulmonary Exacerbations (PA-SCOPE) cohort.We assessed DNA methylation from whole blood samples in 362 African-American smokers in the PA-SCOPE cohort using the Illumina Infinium HumanMethylation27 BeadChip Array. Final analysis included 19302 CpG probes annotated to the nearest gene transcript after quality control. We tested methylation associations with COPD case-control status using mixed linear models. Weighted gene comethylation networks were constructed using weighted gene coexpression network analysis (WGCNA) and network modules were analyzed for association with COPD.There were five differentially methylated CpG probes significantly associated with COPD among African-Americans at an FDR less than 5 %, and seven additional probes that approached significance at an FDR less than 10 %. The top ranked gene association was MAML1, which has been shown to affect NOTCH-dependent angiogenesis in murine lung. Network modeling yielded the "yellow" and "blue" comethylation modules which were significantly associated with COPD (p-value 4?×?10-10 and 4?×?10-9, respectively). The yellow module was enriched for gene sets related to inflammatory pathways known to be relevant to COPD. The blue module contained the top ranked genes in the concurrent differential methylation analysis (FXYD1/LGI4, gene significance p-value 1.2?×?10-26; MAML1, p-value 2.0?×?10-26; CD72, p-value 2.1?×?10-25; and LPO, p-value 7.2?×?10-25), and was significantly associated with lung development processes in Gene Ontology gene-set enrichment analysis.We identified 12 differentially methylated CpG sites associated with COPD that mapped to biologically plausible genes. Network module comethylation patterns have identified candidate genes that may be contributing to racial differences in COPD susceptibility and severity. COPD-associated comethylation modules contained genes previously associated with lung disease and inflammation and recapitulated known COPD-associated genes. The genes implicated by differential methylation and WGCNA analysis may provide mechanistic targets contributing to COPD susceptibility, exacerbations, and outcomes among African-Americans.Trial Registration: NCT00774176 , Registry: ClinicalTrials.gov, URL: www.clinicaltrials.gov , Date of Enrollment of First Participant: June 2004, Date Registered: 04 January 2008 (retrospectively registered).

Dataset Information

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

Publications

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

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