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. 2020 Aug;15(8):871-886.
doi: 10.1080/15592294.2020.1735075. Epub 2020 Mar 9.

Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis

Naveen K Singhal  1 , Sarah Sternbach  1 , Sheila Fleming  2 , Kholoud Alkhayer  1 , John Shelestak  1 , Daniela Popescu  1 , Alyx Weaver  1 , Robert Clements  1 , Brandi Wasek  3 , Teodoro Bottiglieri  3 , Ernest J Freeman  1 , Jennifer McDonough  1
Affiliations

Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis

Naveen K Singhal et al. Epigenetics. 2020 Aug.

Abstract

Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Keywords: BHMT; H3K4me3; betaine; methionine metabolism; mitochondria; multiple sclerosis.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Schematic depicts methionine metabolism and the BHMT-betaine methylation pathway.
Figure 2.
Figure 2.
BHMT is expressed in neurons where it interacts with chromatin and regulates HMT activity.
Figure 3.
Figure 3.
ChIP-seq shows that BHMT is enriched at transcriptional regulators of mitochondrial genes and at mitochondrial genes.
Figure 4.
Figure 4.
The cuprizone mouse model mimics the activation of microglia, increased RNS, and methionine metabolism changes exhibited in MS.
Figure 5.
Figure 5.
Betaine treatment rescues epigenetic control and supports mitochondria.
Figure 6.
Figure 6.
Betaine alleviates sensorimotor disability in cuprizone mice.
Figure 7.
Figure 7.
Model for BHMT-betaine mediated regulation of mitochondrial gene expression.
See this image and copyright information in PMC

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Grants and funding

This work was supported by the Brain Health Institute, Kent State University [Research Award]; and College of Arts and Sciences, Kent State University [Research Award].

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