Transgenerational inheritance of betaine-induced epigenetic alterations in estrogen-responsive IGF-2/IGFBP2 genes in rat hippocampus.

SCOPE: Betaine serves as a methyl donor for DNA methylation. Here, we sought to investigate the effects of betaine on hippocampal expression of neurogenesis genes and their DNA methylation status across three generations.

METHODS AND RESULTS: Pregnant rats (F0) were fed control and betaine-supplemented diets throughout gestation and lactation. Female F1 and F2 offspring at weaning, together with the F0 dams, were used in the study. Hippocampal expression of aromatase, estrogen receptor α and estrogen related receptor β was down-regulated in F1, together with the estrogen-responsive IGF-2/IGFBP2 genes. However, all these genes were up-regulated in F2, which follows the same pattern of F0. In agreement with changes in mRNA expression, the imprinting control region (ICR) of IGF-2 gene was hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all the affected genes was hypermethylated in F1 but hypomethylated in F2 and F0. Methyl transfer enzymes, such as betaine homocysteine methyltransferase and DNA methyltransferase 1, followed the same pattern of transgenerational inheritance.

CONCLUSION: These results indicate that betaine exerts a transgenerational effect on hippocampal expression of estrogen-responsive genes in rat offspring, which is associated with corresponding alterations in DNA methylation on ICR of IGF-2 gene and the promoter of affected genes. This article is protected by copyright. All rights reserved.