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 disease's 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.

Keywords: DNA methylation; epigenetics; multiple sclerosis.

Fig. 1

The major epigenetic mechanisms regulating gene expression. The exon-intron structure of a gene is shown as dark blue and light blue rectangles, respectively. (A) – Methylation of cytosine residues in the CpG island located in the gene promoter region. (B) – The most common modifications of the histone proteins involved in gene expression activation (acetylation of either histone H3 lysine 9 or histone H4 lysine 5 (H3K9ac/H4K5ac) and trimethylation of either histone H3 lysine 3 or histone H3 lysine 4 (H3K4me3/H3K3me3)) and suppression (trimethylation of either histone H3 lysine 9 or histone H3 lysine 27 (H3K9me3/H3K27me3)). (C) – MicroRNA-mediated repression of mRNA translation and degradation

Fig. 2

DNA methylation as an epigenetic mechanism of gene expression regulation (see the text for details). BER – base excision repair; DNMT – DNA methyltransferase; HDAC – histone deacetylase; MBD – methyl- binding domain protein; SAM – S-adenosyl methionine; TET – TET methylcytosine dioxygenase; Rep – repressor protein

Fig. 3

Schematic representation of neurological changes during different clinical courses of MS. The dashed line indicates the neurological deficit level accompanied by clinical manifestations of the disease. The clinically isolated syndrome (CIS) is the first episode of clinical relapse typical of relapsing-remitting MS (RRMS). It can be followed by several years of clinical remission. Repeated relapses followed by periods of remission allow for diagnosing RRMS. Some patients with a prolonged medical history of RRMS develop secondary progressive MS (SPMS) characterized by a steady neurological worsening. Primary progressive MS (PPMS), which is characterized by neurological worsening without remissions from the onset of the disease, is also presented; PPMS manifests itself later than RRMS. The time scale is built based on the mean patient age at the onset of different clinical courses of MS [23, 24, 26]. The number and duration of relapses and remissions are shown schematically