Betaine is a methyl-donor nutrient that can be obtained through the diet and is especially rich in spinach, beets, and whole-wheat foods. Alternatively, betaine can be synthesized from choline obtained through other dietary sources.
Methyl donor nutrients provide precursors for methyl groups used in important biological processes including methyltransferase enzymes which regulate DNA methylation. There is currently great interest in better understanding how dietary methyl donors can effect epigenetics, and whether changes in DNA methylation can be carried from generation to generation.
A recent study by Yang et al. at Nanjing Agricultural University in Nanjing, China aimed to determine if maternal betaine supplementation during pregnancy could alter DNA methylation of the Igf2 and Igfbp2 genes in rats. Igf2 encodes the protein for Insulin like growth factor 2, which is highly involved in many growth processes, not only for the body, but also the brain, where it facilitates neurogenesis and synapse formation.
Igfbp2 encodes a protein which binds to the Igf2 protein and prevents its degradation. The infant period is critical for brain development and formation of synapses, especially in regions such as the hippocampus which is involved in learning and cognition.
The authors found that the first-generation offspring of female rats supplemented with betaine showed reduced bodyweight at birth and weaning, but surprisingly the opposite effect was observed in the second-generation offspring which weighed more at birth and weaning compared to second-generation offspring of control rats.
Betaine supplementation reduced mRNA encoding for the Igf2 and Igfb2 genes in hippocampi of the first-generation but increased expression of these genes in the second generation which may explain these growth trends.
The authors were curious if betaine supplementation altered DNA methylation of promoter regions of the Igf2 gene, which are regions of the gene responsible for activating transcription. Usually, DNA methylation is associated with reduced activation of the gene. Betaine supplementation resulted in increased DNA methylation of promoter sites of the Igf2 gene in the first-generation offspring and reduced promotor methylation in the second-generation offspring.
Igf2 is an estrogen-responsive gene regulated by activation of estrogen receptors, ERα and ERβ. Betaine supplementation reduced expression of ERα and ERβ in the first-generation offspring and increased expression of ERα in the second-generation offspring, suggesting regulation of Igf2 by estrogen receptors.
Furthermore, methylation of promoter regions of the genes encoding for these estrogen receptors was inversely correlated to gene expression which demonstrates that betaine supplementation also resulted in trans-generational modulation of estrogen receptor expression by an epigenetic mechanism.
The results of this study were published in the journal Molecular Nutrition and Food Research and demonstrate that methyl donor supplementation in the diet of maternal rats reduced growth and Igf2 expression in hippocampus of the first-generation offspring and increased growth and hippocampal Igf2 expression in the second-generation offspring. Furthermore, an epigenetic mechanism was shown to be involved where increased methylation of the Igf2 promoter reduced Igf2 expression and subsequently reduced expression of Igf2-target genes.
This study demonstrates that methyl donor intake directly affects physiology of offspring by epigenetic mechanisms. However, scientists studying epigenetic regulation by nutrients still have some legwork to complete before directly applying these results to humans.
The results of this study also leave a few questions unanswered. The authors did not show any histological evidence of impaired hippocampal function or synapse production in the first-generation offspring. Also, no mechanistic explanation was given as to why the first-generation offspring had impaired growth while the second-generation offspring had augmented growth. Future studies determining the mechanism driving epigenetic inheritance of gene expression in response to methyl donor nutrients will be critical in eventually applying the results of these studies to clinically relevant problems.
Source: Yang Y. et al. (2020). Transgenerational Inheritance of Betaine‐Induced Epigenetic Alterations in Estrogen‐Responsive IGF‐2/IGFBP2 Genes in Rat Hippocampus. Molecular Nutrition and Food Research.
Reference: Zeisel S. et al. (2003). Concentrations of Choline-Containing Compounds and Betaine in Common Foods. Journal of Nutrition.