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Review
.2023 Jan 25;24(3):2346.
doi: 10.3390/ijms24032346.

Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection

Affiliations
Review

Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection

Rola A Bekdash. Int J Mol Sci..

Abstract

Methyl donors such as choline, betaine, folic acid, methionine, and vitamins B6 and B12 are critical players in the one-carbon metabolism and have neuroprotective functions. The one-carbon metabolism comprises a series of interconnected chemical pathways that are important for normal cellular functions. Among these pathways are those of the methionine and folate cycles, which contribute to the formation of S-adenosylmethionine (SAM). SAM is the universal methyl donor of methylation reactions such as histone and DNA methylation, two epigenetic mechanisms that regulate gene expression and play roles in human health and disease. Epigenetic mechanisms have been considered a bridge between the effects of environmental factors, such as nutrition, and phenotype. Studies in human and animal models have indicated the importance of the optimal levels of methyl donors on brain health and behavior across the lifespan. Imbalances in the levels of these micronutrients during critical periods of brain development have been linked to epigenetic alterations in the expression of genes that regulate normal brain function. We present studies that support the link between imbalances in the levels of methyl donors, epigenetic alterations, and stress-related disorders. Appropriate levels of these micronutrients should then be monitored at all stages of development for a healthier brain.

Keywords: SAM; brain; epigenetics; methyl donors; stress.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Epigenetics mechanisms. This is a schematic view of the epigenetic mechanisms that regulate gene expression. They are interrelated and include DNA methylation, histone modifications, chromatin remodeling, and the role of microRNAs.
Figure 2
Figure 2
One-carbon metabolism. This figure shows the main components of the one-carbon metabolism, the folate cycle, the methionine cycle, and the contribution of micronutrients such as choline, betaine, folate, methionine, VitB6, and VitB12 in several biological processes. Enzymes and vitamins are written in red and biological processes are highlighted in green. Micronutrients are highlighted in blue. THF: tetrahydrofolate, SAM: S-adenosylmethionine, SHA: S-adenosylhomocysteine, SAHH: SAH hydrolase, BHMT: betaine-homocysteine methyltransferase, MAT: methionine acetyltransferase, DNMTs: DNA methyltransferases, HMTs: histone methyltransferases, MS: methionine synthase, MTHFR: methyltetrahydrofolate reductase, ChAT: choline acetyltransferase, AchE: acetylcholine esterase, GSH: glutathione. Adapted from Ref. [5].
Figure 3
Figure 3
HPA axis. This figure represents the HPA axis or the stress axis where glucocorticoids (GCs) are the outcome of its activation. GC exerts feedback at the levels of the anterior pituitary, hypothalamus, and hippocampus to regulate the stress response. GC receptors are expressed in the hippocampus, hypothalamus, prefrontal cortex, and amygdala, which are considered part of the limbic system. CRF/CRH: corticotropin-releasing hormone or factor, ACTH: adrenocorticotropin hormone, GC: glucocorticoid. Red arrows on the right side mean negative feedback. Green arrow means positive feedback.
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References

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