Reversal of Maternal Programming of Stress Responses in Adult Offspring through Methyl Supplementation: Altering Epigenetic Marking Later in Life

By I. Weaver, F. Champagne, Shelley E. Brown, Sergiy Dymov, Shakti Sharma, Michael Joseph Meaney, M. Szyf. Journal of Neuroscience, 2005

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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. 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 17 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.

Subfields: Molecular Biology, Pediatrics, Perinatology and Child Health, Social Psychology

View Paper: https://www.semanticscholar.org/paper/11797b3e3bd13c62acd17abe091c4801314b22c2

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Citations in the corpus

Fetal programming of hypothalamo‐pituitary‐adrenal function: prenatal stress and glucocorticoids (2006, background): “Interestingly, this effect can be pharmacologically reversed in adulthood (Weaver et al. 2005).”
Epigenetics and the biological definition of gene x environment interactions. (2010, background): “Chromatin-immunoprecipitation assays, which permit measurement of the direct interaction between a specific protein and a defined region of the DNA, reveal increased NGFI-A association with the exon 17 promoter in hippocampi from adult offspring of high- compared to low-LG mothers (Weaver et al., 20”
The neurobiology of stress and development. (2007, background): “These epigenetic effects of maternal care are potentially irreversible , except through pharmacological manipulations that induce widespread demethylation (Weaver et al. 2005).”
Maternal Care and Hippocampal Plasticity: Evidence for Experience-Dependent Structural Plasticity, Altered Synaptic Functioning, and Differential Responsiveness to Glucocorticoids and Stress (2008, background): “As adults, offspring of low compared with high LG mothers show increased hypothalamus-pituitary-adrenal (HPA) responses to stress (Liu et al., 1997; Weaver et al., 2004, 2005), enhanced emotionality (Caldji et al., 1998; Menard and Hakvoort, 2007), and impaired performance in tests of spatial…”
Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis (2007, background): “, 2006) or mother-child interactions (see Meaney & Szyf, 2005; Weaver et al., 2005) that can produce profound epigenetic changes as shown in proof-of-principle studies in animals.”
Autism and Increased Paternal Age Related Changes in Global Levels of Gene Expression Regulation (2011, neutral): “expression regulation [14,15,16,17,18,19].”
Prenatal environmental exposures, epigenetics, and disease (2011, neutral): “[38,39] showing that maternal stress and subsequent nurturing behaviors alter the epigenotype in rodent offspring, affecting their glucocorticoid receptor (GR) expression and behavior.”
Maternal adversity and ecological stressors in natural populations: the role of stress axis programming in individuals, with implications for populations and communities (2013, background): “Weaver and colleagues showed that maternal care altered DNA methylation in the offspring at a GR gene promoter in the hippocampus by inhibiting the binding of NGFI-A, a transcription factor that drives GR expression (Weaver et al. 2004, 2005, 2007; Fig.”
Prenatal Stress, Glucocorticoids and the Programming of Adult Disease (2009, background): “The higher levels of GR in high-LG offspring can be reduced by the administration of the methyl donor S-adenosyl-methionine (SAM), through increased DNA methylation of exon 1 7 (Weaver et al., 2005).”