Reversal of Maternal Programming of Stress Responses in Adult Offspring Through Methyl Supplementation

Moshe Szyf
Department of Pharmacology and Therapeutics ; McGill University

Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 17 glucocorticoid receptor (GR) promoter [1]. 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 (AdoMet) that serves as the donor of methyl-groups for DNA methylation and inhibits active demethylation by demethylases [2]. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, NGFI-A binding to the exon 17 promoter, GR expression and hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stress, suggesting a causal relation among epigenomic state, GR expression and stress responses in the adult offspring. Interestingly, the effects of methionine were independent of histone H3-K9 acetylation. These results demonstrate that in spite of the inherent stability of the epigenomic marks established early in life through behavioral programming, they are dynamically maintained and potentially reversible in the adult brain by altering the concentration of one essential amino acid.


  1. Weaver, I.C. Cervoni, N. Champagne, F. A. D'Alessio, A. C. Sharma, S. Dymov, S. Szyf, M., and Meaney, MJ. Epigenetic programming by maternal behavior. Nat. Neurosci. 7: 847-854, 2004.

  2. Detich, N. Hamm, S., Just, G., Knox, J.D., and Szyf, M. The methyl donor S-Adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-Adenosylmethionine. J. Biol. Chem. 278, 20812-20820, 2003.