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DNA Methylation: a New Player in Multiple Sclerosis

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Abstract

Multiple sclerosis (MS) is a neurological and chronic inflammatory disease that is mediated by demyelination and axonal degeneration in the central nervous system (CNS). Studies have shown that immune system components such as CD4+, CD8+, CD44+ T cells, B lymphatic cells, and inflammatory cytokines play a critical role in inflammatory processes and myelin damage associated with MS. Nevertheless, the pathogenesis of MS remains poorly defined. DNA methylation, a significant epigenetic modification, is reported to be extensively involved in MS pathogenesis through the regulation of gene expression. This review focuses on DNA methylation involved in MS pathogenesis. Evidence showed the hypermethylation of human leukocyte antigen-DRB1 (HLA-DRB1) in CD4+ T cells, the genome-wide DNA methylation in CD8+ T cells, the hypermethylation of interleukin-4 (IL-4)/forkhead winged helix transcription factor 3 (Foxp3), and the demethylation of interferon-γ (IFN-γ)/IL-17a in CD44+ encephalitogenic T cells. Studies also showed the hypermethylation of SH2-containing protein tyrosine phosphatase-1 (SHP-1) in peripheral blood mononuclear cells (PBMCs) and methylated changes of genes regulating oligodendrocyte and neuronal function in normal-appearing white matter. Clarifying the mechanism of aberrant methylation on MS may explain part of the pathology and will lead to the development of a new therapeutic target for the treatment of MS in the future.

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Abbreviations

5hmC:

5-Hydroxymethylcytosine

5mC:

5-Methylcytosine

APC:

Antigen-presenting cell

BBB:

Blood-brain barrier

BCL2L2:

Bcl-2-like protein 2

CIS:

Clinically isolated syndrome

CNS:

Central nervous system

Co-rep:

Co-repressors

CTSZ:

Cathepsin z

DNHD1:

Dynein heavy chain domain 1

Dnmts:

DNA methyltransferases

EAE:

Experimental autoimmune encephalomyelitis

EBV:

Epstein-Barr virus

Foxp3:

Forkhead winged helix transcription factor-3

HAGHL:

Hydroxyacylglutathione hydrolase-like

HDACs:

Histone deacetylases

HERV-W:

Human endogenous retrovirus W

HLA-DRB1:

Human leukocyte antigen-DRB1

Hlx:

H2.0-like homeobox

IFN-γ:

Interferon-γ

IL:

Interleukin

LGMN:

Legumain

MBDs:

Methyl-binding domain proteins

MBP:

Myelin basic protein

MeCP2:

Methyl-CpG-binding protein 2

MHC:

Major histocompatibility complex

MHC2TA:

MHC class II transactivator

MOG:

Myelin oligodendrocyte glycoprotein

MS:

Multiple sclerosis

NAWM:

Normal-appearing white matter

NDRG1:

N-myc downstream regulated gene 1

OPCs:

Oligodendrocyte precursors

PAD2/4:

Peptidyl arginine deiminase 2/4

PBMCs:

Peripheral blood mononuclear cells

PPMS:

Primary-progressive multiple sclerosis

RIS:

Radiologically isolated syndrome

RPS2:

Ribosomal protein S2

RRMS:

Relapsing-remitting multiple sclerosis

SHP-1:

SH2-containing protein tyrosine phosphatase-1

TCF-1:

T-cell factor-1

TNFα:

Tumor necrosis factor α

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 31100771) and Postdoctoral Foundation of CQ CSTC (2011018). Thanks are extended to Professor Lan Xiao for giving advice on revising this review and to Professor Min Yang and Zhi-fang Li for their help in correcting the language.

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  1. Department of Histology and Embryology, Faculty of Basic Medicine, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, China

    Xiang Li, Bing Xiao & Xing-Shu Chen

  2. The Thirteenth Camp of Cadet Brigade, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, China

    Xiang Li

  3. The Eleventh Camp of Cadet Brigade, Third Military Medical University, No. 30 Gaotanyan Street, Chongqing, 400038, China

    Bing Xiao

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  1. Xiang Li
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Li, X., Xiao, B. & Chen, XS. DNA Methylation: a New Player in Multiple Sclerosis. Mol Neurobiol 54, 4049–4059 (2017). https://doi.org/10.1007/s12035-016-9966-3

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