通过补充甲基逆转成年后代应激反应的母体编程:在生命后期改变表观遗传标记
Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.
作者信息
Weaver Ian C G, Champagne Frances A, Brown Shelley E, Dymov Sergiy, Sharma Shakti, Meaney Michael J, Szyf Moshe
机构信息
Douglas Hospital Research Center, Montréal, Québec H4H 1R3, Canada.
出版信息
J Neurosci. 2005 Nov 23;25(47):11045-54. doi: 10.1523/JNEUROSCI.3652-05.2005.
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.
成年大鼠的应激反应在生命早期由母性照料编程,并与海马外显子1(7)糖皮质激素受体(GR)启动子的表观基因组标记相关。为了研究这种表观遗传编程在成年期是否可逆,我们向成年后代脑内注入必需氨基酸L-甲硫氨酸,它是S-腺苷甲硫氨酸的前体,而S-腺苷甲硫氨酸作为DNA甲基化的甲基供体。我们在此报告,甲硫氨酸注入可逆转母性行为对DNA甲基化、神经生长因子诱导蛋白-A与外显子1(7)启动子的结合、GR表达以及下丘脑-垂体-肾上腺对应激的反应和行为反应的影响,提示成年后代表观基因组状态、GR表达和应激反应之间存在因果关系。这些结果表明,尽管通过行为编程在生命早期建立的表观基因组标记具有内在稳定性,但它们在成年大脑中可能是可逆的。