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  • Review Article
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Epigenetic changes in patients with multiple sclerosis

Nature Reviews Neurology volume 9, pages 35–43 (2013)Cite this article

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Abstract

Epigenetic changes influence gene expression without altering the DNA sequence. DNA methylation, histone modification and microRNA-associated post-transcriptional gene silencing are three key epigenetic mechanisms. Multiple sclerosis (MS) is a disease of the CNS with both inflammatory and neurodegenerative features. Although studies on epigenetic changes in MS only began in the past decade, a growing body of literature suggests that epigenetic changes may be involved in the development of MS, possibly by mediating the effects of environmental risk factors, such as smoking, vitamin D deficiency and Epstein–Barr virus infection. Such studies are also beginning to deliver important insights into the pathophysiology of MS. For example, inflammation and demyelination in relapsing–remitting MS may be related to the increased differentiation of T cells toward a T-helper 17 phenotype, which is an important epigenetically regulated pathophysiological mechanism. In progressive MS, other epigenetically regulated mechanisms, such as increased histone acetylation and citrullination of myelin basic protein, might exacerbate the disease course. In this Review, we summarize current knowledge on the role of epigenetic changes in the pathophysiology of MS.

Key Points

  • Multiple sclerosis (MS) has both inflammatory and neurodegenerative characteristics, with striking interindividual differences in disease course and severity

  • A low concordance rate for MS in monozygotic twins and enhanced maternal transmission of risk alleles suggest that epigenetic changes influence MS susceptibility

  • The effects of environmental risk factors, such as smoking, vitamin D level and Epstein–Barr virus infection, on the development and course of MS might be mediated by epigenetic mechanisms

  • In patients with relapsing–remitting MS, macrophage activation and differentiation of T-helper 17 cells are important epigenetically regulated proinflammatory mechanisms

  • In patients with progressive MS, citrullination of myelin basic protein and CNS neurosteroid synthesis are important epigenetically regulated neurodegenerative mechanisms

  • Future therapies for MS that target these epigenetic mechanisms might utilize histone deacetylase inhibitors, DNA methyltransferase inhibitors, and oligonucleotides containing modified locked nucleic acids

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Figure 1: DNA methylation.
Figure 2: Translational repression of proteins by miRNAs.
Figure 3: Epigenetic control of TH17-cell differentiation by miR-326.
Figure 4: Epigenetic regulation of PAD2 expression in MS involves DNA methylation.
Figure 5: Silencing of neurosteroid synthesis by miR-155, miR-338 and miR-491.

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Authors and Affiliations

  1. Department of Clinical Neurosciences, University of Calgary, Foothills Hospital, 1403–29th Street N. W., Calgary, T2N 2T9, AB, Canada

    Marcus W. Koch & Luanne M. Metz

  2. Department of Biology, University of Lethbridge, 4401 University Drive, Lethbridge, T1K 3M4, AB, Canada

    Olga Kovalchuk

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M. W. Koch and O. Kovalchuk researched data for the article. M. W. Koch, L. M. Metz and O. Kovalchuk provided substantial contributions to discussion of the article, writing and review and/or editing before submission of the manuscript.

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Koch, M., Metz, L. & Kovalchuk, O. Epigenetic changes in patients with multiple sclerosis. Nat Rev Neurol 9, 35–43 (2013). https://doi.org/10.1038/nrneurol.2012.226

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