Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA

Webb, Lindsay M.; Guerau-de-Arellano, Mireia

doi:10.1016/j.molmed.2017.04.004

Cited by 20 publications

(9 citation statements)

References 109 publications

(172 reference statements)

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“…One way T cell responses can be dampened in EAE is through pan-methylation inhibitors. Treatment with these inhibitors has been linked to reduced EAE clinical scores and T cell responses (12)(13)(14). PRMT5 is the main protein involved in symmetric dimethylation (15).…”

Section: Introductionmentioning

confidence: 99%

PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

2021

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Multiple Sclerosis (MS) is a debilitating central nervous system disorder associated with inflammatory T cells. Activation and expansion of inflammatory T cells is thought to be behind MS relapses and influence disease severity. Protein arginine N-methyltransferase 5 (PRMT5) is a T cell activation-induced enzyme that symmetrically dimethylates proteins and promotes T cell proliferation. However, the mechanism behind PRMT5-mediated control of T cell proliferation and whether PRMT5 contributes to diseases severity is unclear. Here, we evaluated the role of PRMT5 on cyclin/cdk pairs and cell cycle progression, as well as PRMT5’s link to disease severity in an animal model of relapsing-remitting MS. Treatment of T helper 1 (mTh1) cells with the selective PRMT5 inhibitor, HLCL65, arrested activation-induced T cell proliferation at the G1 stage of the cell cycle, suggesting PRMT5 promotes cell cycle progression in CD4+ T cells. The Cyclin E1/Cdk2 pair promoting G1/S progression was also decreased after PRMT5 inhibition, as was the phosphorylation of retinoblastoma. In the SJL mouse relapsing-remitting model of MS, the highest PRMT5 expression in central nervous system-infiltrating cells corresponded to peak and relapse timepoints. PRMT5 expression also positively correlated with increasing CD4 Th cell composition, disease severity and Cyclin E1 expression. These data indicate that PRMT5 promotes G1/S cell cycle progression and suggest that this effect influences disease severity and/or progression in the animal model of MS. Modulating PRMT5 levels may be useful for controlling T cell expansion in T cell-mediated diseases including MS.

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Section: Introductionmentioning

confidence: 99%

PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

2021

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“…The discovery that 1,25(OH)2D3 rapidly increased flux through the MET cycle is significant in the context of emerging evidence that the MET cycle is impaired in MS patients [207]. The BHMT gene sequence is conserved in Immunometabolism.…”

Section: Diminished Gene Expressionmentioning

confidence: 99%

Multiple Sclerosis: Lipids, Lymphocytes, and Vitamin D

Hayes

Ntambi

2020

Immunometabolism

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We review the two core MS features, myelin instability, fragmentation, and remyelination failure, and dominance of pathogenic CD4 + Th17 cells over protective CD4 + Treg cells. To better understand myelin pathology, we describe myelin biosynthesis, structure, and function, then highlight stearoyl-CoA desaturase (SCD) in nervonic acid biosynthesis and nervonic acid's contribution to myelin stability. Noting that vitamin D deficiency decreases SCD in the periphery, we propose it also decreases SCD in oligodendrocytes, disrupting the nervonic acid supply and causing myelin instability and fragmentation. To better understand the distorted Th17/Treg cell balance, we summarize Th17 cell contributions to MS pathogenesis, then highlight how 1,25dihydroxyvitamin D3 signaling from microglia to CD4 + T cells restores Treg cell dominance. This signaling rapidly increases flux through the methionine cycle, removing homocysteine, replenishing S-adenosylmethionine, and improving epigenetic marking. Noting that DNA hypomethylation and inappropriate DRB1*1501 expression were observed in MS patient CD4 + T cells, we propose that vitamin D deficiency thwarts epigenetic downregulation of DRB1*1501 and Th17 cell signature genes, and upregulation of Treg cell signature genes, causing dysregulation within the CD4 + T cell compartment. We explain how obesity reduces vitamin D status, and how estrogen and vitamin D collaborate to promote Treg cell dominance in females. Finally, we discuss the implications of this new knowledge concerning myelin and the Th17/Treg cell balance, and advocate for efforts to address the global epidemics of obesity and vitamin D deficiency in the expectation of reducing the impact of MS.

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“…Decreases in the methyl donor betaine were correlated with reduced levels of histone H3 trimethylation (H3K4me3) in NeuN+ neuronal nuclei in the MS cortex, which may downregulate expression of metabolic genes in neurons (Singhal et al, 2015). Thus, methionine metabolism and methylation may be linked to abnormal neuronal metabolisms and neurodegeneration in MS (Singhal et al, 2015; Webb and Guerau-de-Arellano, 2017).…”

Section: Histone Modifying Enzymes In Oligodendrocyte Developmentmentioning

confidence: 99%

Chromatin remodeling and epigenetic regulation of oligodendrocyte myelination and myelin repair

Koreman

Sun

Lü

2018

Molecular and Cellular Neuroscience

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Oligodendrocytes are essential for the development, function, and health of the vertebrate central nervous system. These cells maintain axon myelination to ensure saltatory propagation of action potentials. Oligodendrocyte develops from neural progenitor cells, in a step-wise process that involves oligodendrocyte precursor specification, proliferation, and differentiation. The lineage progression requires coordination of transcriptional and epigenetic circuits to mediate the stage-specific intricacies of oligodendrocyte development. Epigenetic mechanisms involve DNA methylation, histone modifications, ATP-dependent chromatin remodeling, and non-coding RNA modulation that regulate the chromatin state over regulatory genes, which must be expressed or repressed to establish oligodendrocyte identity and lineage progression. In this review, we will focus on epigenetic programming associated with histone modification enzymes, chromatin remodeling, and non-coding RNAs that regulate oligodendrocyte lineage progression, and discuss how these mechanisms might be harnessed to induce myelin repair for treatment of demyelinating diseases such as multiple sclerosis.

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Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA

Cited by 20 publications

References 109 publications

PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

Multiple Sclerosis: Lipids, Lymphocytes, and Vitamin D

Chromatin remodeling and epigenetic regulation of oligodendrocyte myelination and myelin repair

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