DNA Methylation As an Epigenetic Mechanism in the Development of Multiple Sclerosis

Abstract

The epigenetic mechanisms of gene expression regulation are a group of the key cellular and molecular pathways that lead to inherited alterations in genes activity without changing their coding sequence. DNA methylation at the C5 position of cytosine in CpG dinucleotides is amongst the central epigenetic mechanisms. Currently, the number of studies that are devoted to the identification of methylation patterns specific to multiple sclerosis (MS), a severe chronic autoimmune disease of the central nervous system, is on a rapid rise. However, the issue of the contribution of DNA methylation to the development of the different clinical phenotypes of this highly heterogeneous disease has only begun to attract the attention of researchers. This review summarizes the data on the molecular mechanisms underlying DNA methylation and the MS risk factors that can affect the DNA methylation profile and, thereby, modulate the expression of the genes involved in the diseases pathogenesis. The focus of our attention is centered on the analysis of the published data on the differential methylation of DNA from various biological samples of MS patients obtained using both the candidate gene approach and high-throughput methods.

Genome-wide DNA methylation profiling identifies epigenetic changes in CD4+ and CD14+ cells of multiple sclerosis patients

“…An increasing number of studies are now focusing on the identification of epigenetic changes that cause long-lasting alterations of gene expression in different cell populations, and, as a consequence, the development of various pathological processes. Recent studies have shown that DNA methylation of various blood components (serum, PBMCs, CD4+ and CD8+ T-lymphocytes, CD19+ B-lymphocytes, CD14+ monocytes) may be involved in the development of MS (reviewed in Kiselev et al 2021). Genome-wide DNA methylation profiling of CD4+ and CD14+ cells, performed in the present work, expands a limited series оf analyses of DNA methylation in different leucocyte populations.…”

“…For example, most studies investigated DNA methylation levels in MS groups, which included not only never-treated patients, but also patients who received various immunomodulatory drugs before and/or during blood sampling, despite the fact that drug therapy was shown to affect methylation level in blood cells (Maltby et al, 2018b). In fact, locus HLA is the only genomic region, differential methylation of which has been consistently validated in whole blood and several sorted immune cell types (Kiselev et al, 2021).…”

“…However, according to different estimates, contribution of all identified to date MS-associated variants can explain not more than 48% of the disease heritability (International Multiple Sclerosis Genetics Consortium, 2019). Epigenetic modifications, which cause long-lasting alterations of gene expression in various cells and tissues without changes in DNA sequence, should be also investigated to improve the understanding of MS molecular mechanisms.DNA methylation of CpG dinucleotides in the C5 position of a cytosine ring is one of the most stable and well-studied epigenetic modifications that regulates expression of the nearest genes through different mechanisms (Kiselev et al, 2021). DNA methylation may be affected by environmental triggers of MS, such as viral infections or smoking Abbreviations: DMP, differentially methylated position; MS, multiple sclerosis; PBMCs, peripheral blood mononuclear cells.…”

“…DNA methylation of CpG dinucleotides in the C5 position of a cytosine ring is one of the most stable and well-studied epigenetic modifications that regulates expression of the nearest genes through different mechanisms (Kiselev et al, 2021). DNA methylation may be affected by environmental triggers of MS, such as viral infections or smoking Abbreviations: DMP, differentially methylated position; MS, multiple sclerosis; PBMCs, peripheral blood mononuclear cells.…”

Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis

“…Contrary to aging, methylation appears to be globally increased in MS [reviewed by (229)], with different methylation profiles between MS phenotypes, higher in PPMS compared to RRMS (230), but slightly higher in RRMS compared to SPMS (231). Lymphocyte signaling, T cell activation and migration were common pathways to RRMS and SPMS methylation profiles, while myeloid cell function and neuronal and neurodegenerative genes and pathways were SPMS-specific (231).…”