1. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.
- Author
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Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, and Szyf M
- Subjects
- Aging, Animals, Animals, Newborn, Behavior, Animal, Early Growth Response Protein 1 metabolism, Female, Hypothalamo-Hypophyseal System physiopathology, Methionine pharmacology, Pituitary-Adrenal System physiopathology, Promoter Regions, Genetic, Rats, Rats, Long-Evans, Receptors, Glucocorticoid metabolism, Stress, Physiological psychology, DNA Methylation drug effects, Epigenesis, Genetic, Hippocampus metabolism, Maternal Behavior, Receptors, Glucocorticoid genetics, Stress, Physiological physiopathology
- Abstract
Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 1(7) glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acid L-methionine, a precursor to S-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 1(7) promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible in the adult brain.
- Published
- 2005
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