Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.
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.
Weaver
Ian C G
IC
Douglas Hospital Research Center, Montréal, Québec H4H 1R3, Canada.
Champagne
Frances A
FA
Brown
Shelley E
SE
Dymov
Sergiy
S
Sharma
Shakti
S
Meaney
Michael J
MJ
Szyf
Moshe
M
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D019175:DNA Methylation / Q000187:drug effects*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008425:Maternal Behavior; D008715:Methionine / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D051381:Rats; D020318:Rats, Long-Evans; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000503:physiopathology* / Q000523:psychology
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D011965:Receptors, Glucocorticoid; D008715:Methionine