Epigenetic Mechanisms for the Early Environmental Regulation of Hippocampal Glucocorticoid Receptor Gene Expression in Rodents and Humans
Open accessAbstract
Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamic-pituitary-adrenal responses to stress compared with the offspring of low LG mothers. In humans, childhood maltreatment associates decreased hippocampal GR expression and increased stress responses in adulthood. We review the evidence suggesting that such effects are mediated by epigenetic mechanisms, including DNA methylation and hydroxymethylation across GR promoter regions. We also present new findings revealing associated histone post-translational modifications of a critical GR promoter in rat hippocampus. Taken together these existing evidences are consistent with the idea that parental influences establish stable phenotypic variation in the offspring through effects on intracellular signaling pathways that regulate the epigenetic state and function of specific regions of the genome.
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Some overlap exists between MDD-associated differentially methylated regions in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.
“Previous work indicates some overlap between MDD-associated differentially methylated regions (DMRs) in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.82–85”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [85]
The Summary (page unavailable) discusses environmental effects on hippocampal glucocorticoid-receptor methylation, and the section on developmental regulation in humans discusses hippocampal findings related to depression. Neither reports an overlap between MDD-associated DMRs in blood and those in the prefrontal cortex or other brain regions. Searches for that overlap, blood–brain methylation comparisons, and prefrontal cortex found no supporting passage in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredThe level of 5-hydroxymethylcytosine of the exon 17 GR promoter was three times higher in hippocampal samples from offspring of Low compared with High-LG mothers.
“We analyzed levels of 5-hydroxymethylcytosine and 5-methylcytosine across the hippocampal GR exon 17 promoter in rats using antibody capture of hippocampal DNA and found the level of 5-hydroxymethylcytosine of the exon 17 GR promoter was three times higher in hippocampal samples from the offspring of Low compared with High-LG mothers.92”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [92]
Across the exon 17 GR promoter, decreased DNA methylation was associated with increased H3K4me3.
“The same relation was apparent across the exon 17 GR promoter, where the decreased level of DNA methylation was associated with an increased level of H3K4me3.92”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [92]
5-methylcytosine-dependent immunoprecipitation revealed no differences across the exon 17 GR promoter.
“In contrast, 5-methylcytosine-dependent immunoprecipitation revealed no differences across the exon 17 GR promoter.”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [92]
There is increased H3K9ac and H3K4me3 at both regions of the exon 17 GR promoter, and the levels of these marks are very highly correlated.
“Thus we find increased H3K9ac and H3K4me3 at both regions of the exon 17 GR promoter, and the levels of these individual marks are very highly correlated.92”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [92]
There is increased H3K9ac of the exon 17 GR promoter in hippocampus from adult offspring of High compared with Low LG mothers.
“H3K9ac associates with increased transcription and we found increased H3K9ac of the exon 17 GR promoter in hippocampus from the adult offspring of High compared with Low LG mothers.70,83,92”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [92]
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References 171 · Cited by 347
Research works printed but not linked: 3
- Maestripieri D, Mateo J (2009). Maternal effects in mammals . In: Maestripieri D, Mateo JM (eds). The University of Chicago Press: Chicago.
- Sroufe LA (1997). Emotional Development. Cambridge University Press: Cambridge UK.
- Turner BM (2001). Chromatin Structure and the Regulation of Gene Expression . Blackwell Science Ltd.: Oxford.
- Authors
- Zhang, T. Y., Labonté, B., Wen, X. L., Turecki, G., & Meaney, M. J.
- Affiliations
- McGill University (CA)
- Singapore Institute for Clinical Sciences (SG)
- Corresponding author
- Meaney, Michael J
- Venue
- Neuropsychopharmacology
- Published
- 2012-09-12
- Volume
- 38
- Issue
- 1
- Pages
- 111-123
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3521971
- OpenAlex
- W2162016125
- Cited by
- 347
- References
- 171
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 12 · 2023: 12 · 2022: 18 · 2021: 12 · 2020: 47 · 2019: 22 · 2018: 26 · 2017: 25 · 2016: 41 · 2015: 37 · 2014: 50 · 2013: 25 · 2012: 2
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-04-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- glucocorticoid receptor, hippocampus, epigenetics, DNA methylation, hydroxymethylation, histone modifications, parental care, child abuse, stress reactivity, hypothalamic-pituitary-adrenal axis, mood disorders, gene expression regulation
- MeSH terms
- Animals, Gene Expression Regulation, Hippocampus, Humans, Maternal Behavior, Receptors, Glucocorticoid, Social Environment, Epigenesis, Genetic, Rats
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