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

Abstract

Background Systemic sclerosis (SSc) is a multisystem autoimmune disorder that has an unclear etiology and disproportionately affects women and African Americans. Despite this, African Americans are dramatically underrepresented in SSc research. Additionally, monocytes show heightened activation in SSc and in African Americans relative to European Americans. In this study, we sought to investigate DNA methylation and gene expression patterns in classical monocytes in a health disparity population. Methods Classical monocytes (CD14+ + CD16−) were FACS-isolated from 34 self-reported African American women. Samples from 12 SSc patients and 12 healthy controls were hybridized on MethylationEPIC BeadChip array, while RNA-seq was performed on 16 SSc patients and 18 healthy controls. Analyses were computed to identify differentially methylated CpGs (DMCs), differentially expressed genes (DEGs), and CpGs associated with changes in gene expression (eQTM analysis). Results We observed modest DNA methylation and gene expression differences between cases and controls. The genes harboring the top DMCs, the top DEGs, as well as the top eQTM loci were enriched for metabolic processes. Genes involved in immune processes and pathways showed a weak upregulation in the transcriptomic analysis. While many genes were newly identified, several other have been previously reported as differentially methylated or expressed in different blood cells from patients with SSc, supporting for their potential dysregulation in SSc. Conclusions While contrasting with results found in other blood cell types in largely European-descent groups, the results of this study support that variation in DNA methylation and gene expression exists among different cell types and individuals of different genetic, clinical, social, and environmental backgrounds. This finding supports the importance of including diverse, well-characterized patients to understand the different roles of DNA methylation and gene expression variability in the dysregulation of classical monocytes in diverse populations, which might help explaining the health disparities.

Recent Insights into the Role of DNA Methylation and Histone Modifications in Systemic Sclerosis: A Scoping Review

“…We identified only one study to analyze isolated monocytes from SSc patients [ 49 ]. The results from this study in which the authors analyzed a population of African American patients with SSc using a genome-wide DNA methylation assay demonstrated modest DNA methylation and gene expression differences between SSc patients and healthy controls.…”

“…Additionally, this scoping review identified studies that discovered epigenetic alterations in cells of the innate immune system, including monocytes [ 22 , 49 ], DCs and pDCs [ 17 , 50 ], which highlight their role in SSc pathogenesis. Studies on PTMs in monocytes discovered altered chromatin marks that correlate with the IFN signature observed in these cells.…”

“…References [ 64 , 65 , 66 ] are cited only in Supplementary Table S1. References [ 19 , 29 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 61 , 64 , 65 , 66 ] are cited in the main text and in Supplementary Table S1.…”