Background: Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system with a strong autoimmune component. More than 200 genetic variants have been associated to MS using GWAS studies and transcriptional studies have revealed specific transcriptional signatures in peripheral immune cells at different stages of MS. Yet, it is not clear how environmental factors interact with these molecular mechanisms in MS. Here we ask whether epigenetic chromatin signatures are altered in MS and to what extent open chromatin regions are associated with the concurrent genetic and transcriptional events.
Objectives: To characterize chromatin signatures associated with inflammation and MS risk SNPs in newly diagnosed and untreated MS patients. To this end, we generated paired chromatin accessibility (ATAC-Seq) and transcriptomic (RNA-seq) profiles of blood derived immune cells namely CD4 and CD8 T cells, CD14 monocytes and CD19 B cells from healthy donors (HC) and MS patients.
Results: We identified 106, 30, 13 and 203 regions with differential accessibility between MS and HC in CD4, CD8, CD14 and CD19 cells respectively (pval< 0.05). Transcription factors binding these regions primarily consisted on zinc finger binding proteins known to play a role in transcription regulation and were seen primarily in CD4 (Fisher's exact test, pval< 0.05). In addition, using a sampling algorithm we found these regions to be enriched in MS GWAS regions and MS differentially methylated loci, again primarily in CD4 and CD19 (pval< 0.05). The transcriptomic profiles of the 4 cell types showed differential expression of 74 genes in only CD4 cells (FDR< 0.2). Functionally these genes were immune and transcription related in nature. Overlap of these genes with differentially accessible regions resulted in SERTAD1, a gene previously reported in transcriptomic and methylation studies in MS.
Conclusion: Taken together, these findings provide additional evidence for the primary role of T cells in MS, along with insights into the growing documented importance of B cells in MS. Also, we find additional evidence for the differential regulation of SERTAD1 in MS in CD4 T cells. This gene is also found differentially expressed in PBMCs in other neurological disease and depression.
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