Epigenetics in multiple sclerosis

Abstract

The development of multiple sclerosis (MS) is based on complex interactions between genetic and environmental factors. Epigenetic regulation is a biological phenomenon defined as the modification of gene expression without alteration of the DNA sequence, and is currently thought to underlie the interactions between the genetic and environmental risks of MS. The molecular mechanisms of epigenetics include DNA methylation, histone modification, and microRNAs. Observational data obtained from epidemiological studies of MS, such as the parent-of-origin effect and the longitudinal increase in female patients, suggest that epigenetic mechanisms are involved in MS development, although the molecular basis remains unclear. Interestingly, environmental factors related to the development of MS, such as Epstein-Barr virus, smoking, and vitamin D, have been shown to regulate gene expression through epigenetic mechanisms in some experimental settings. One study showed no reproducible differences among DNA methylation profiles in peripheral blood CD4 + T cells between three monozygotic twin pairs discordant for MS. However, several studies have shown that dysregulated DNA methylation of genes is related to abnormal immune reactions and post-translational modifications of myelin proteins in MS brain samples. In addition, abnormal microRNA profiles have been reported in brain tissues and peripheral blood immune cells obtained from MS patients. In this article, we will review the studies on the epigenetics of MS and discuss the perspectives for future research.

Endogenous type I interferons and their regulators in multiple sclerosis

“…Furthermore, regulatory T cells deficient in miR‐146a have impaired suppressive functions . Although miR‐146a is reported to be upregulated in MS, its significance in MS is not clear …”

“…In contrast, upregulation of miR‐221/222 in several tumor cells suppresses STAT1 and STAT2, and helps tumor cells to evade immune surveillance . Among the miRNA involved in the regulation of type I IFN responses, miR‐155 deserves attention as one of the best‐known miRNA involved in the immune responses, and the most frequently reported miRNA upregulated in MS . The importance of miR‐155 in MS is further supported by its dysregulation in multiple cell populations involved in MS pathology, including T cells, B cells, monocytes, microglia, astrocytes and vascular endothelial cells .…”

“…Among the miRNA involved in the regulation of type I IFN responses, miR‐155 deserves attention as one of the best‐known miRNA involved in the immune responses, and the most frequently reported miRNA upregulated in MS . The importance of miR‐155 in MS is further supported by its dysregulation in multiple cell populations involved in MS pathology, including T cells, B cells, monocytes, microglia, astrocytes and vascular endothelial cells . miR‐155 KO mice are resistant to EAE induction, because Th17 induction is reduced .…”

Deciphering the role of DNA methylation in multiple sclerosis: emerging issues

“…Histone alterations include several procedures that regulate transcription, such as acetylation and phosphorylation. Acetylation of the N-terminal tail of a histone leads to decompression of chromatin and upregulates transcription [ 3 ]. Micro-RNAs are single stranded, small in nucleotide amount RNAs, which do not encode any proteins.…”

“…A number of explanations may account for the discordant findings. Tissue specificity in DNA methylation, the epigenetic changes induced as a result of aging, the possible inability of detecting loci with low methylation changes, the limited sample size, the diversity in methodology, and the tested MS clinical phenotypes could explain, at least in part, the discordance of results among the studies [ 3 , 31 ]. Purified cell populations should be preferred from mixtures of cells to receive tissue specific epigenetic profile.…”