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Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse
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Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.
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“Also, in the same group there was decreased NGF1-A transcription factor binding and NGF1-induced gene transcription (137).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [137]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“McGowan et al. first demonstrated this in post-mortem hippocampal samples of suicide victims with a history of childhood abuse, showing methylation levels approximately 2-fold higher at key CpG sites than in controls (55).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [55]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“One of the most consistent findings in suicide research is hypermethylation of specific CpG sites in the NR3C1 promoter region, particularly exon 1F, which reduces glucocorticoid receptor expression and disrupts negative feedback within the HPA axis (55).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [55]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Genetic liability and early-life adversity converge on glucocorticoid signaling. Polymorphisms in NR3C1 and FKBP5 alter glucocorticoid receptor sensitivity, while childhood maltreatment produces stable hypermethylation of the NR3C1 promoter that further reduces glucocorticoid feedback (55).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [55]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Childhood maltreatment, including abuse and neglect, represents a sustained early-life stressor associated with long-term biological and behavioral changes across generations.”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [119]
Experimental — accuracy not yet measured
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In the citing paper
“Altered methylation of genes involved in HPA-axis feedback and glucocorticoid homeostasis, including NR3C1 and FKBP5, has been reported in individuals with histories of abuse or neglect (118–120).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [119]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Evidence suggests involvement of stress-response regulation, neurodevelopmental and emotional processing pathways, and epigenetic remodeling processes in shaping intergenerational outcomes (116–124).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [119]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In the case of early-life stress, commonly experienced through childhood abuse, DNA methylation of stress-regulating genes (i.e. NR3C1, FKBP5) increases, hypermethylating the glucocorticoid receptor and altering the HPA axis”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The first documented study of the GR promoter in humans showed higher methylation of the hippocampal GR 1F promoter in post-mortem tissue of adult suicide victims with a history of childhood abuse, similar to findings in rodent pups raised by mothers who provided low levels of licking and grooming 121,122 .”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [121]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In postmortem brain tissue (hippocampus) from those who have died by suicide, there was decreased expression of GRs, along with enhanced cytosine methylation of the NR3C1 promoter in those with a history of childhood trauma.”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [137]
The cited source says what the claim attributes to it.
In the citing paper
“and regulates the stress response through both genetic (136) and epigenetic mechanisms (137).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [137]
The cited source says what the claim attributes to it.
In the citing paper
“For example, in a recent human brain autopsy material study, history of childhood abuse was associated with changes in DNA methylation related to the neuron-specific GR (NR3C1) promoter in the hippocampus, suggesting distinct effects of ELS/CT on the epigenetic regulation of hippocampal GR expression (405).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [405]
The cited source says what the claim attributes to it.
In the citing paper
“Lower GR expression along with higher levels of cytosine methylation of the GR promoter exon 1 F have been reported in suicide decedents with a history of childhood abuse than in suicide decedents without a history of abuse as well as in non-suicide controls.78”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [78]
The cited source says what the claim attributes to it.
In the citing paper
“Reduced expression was linked to increased hippocampal NR3C1 1 F promoter CpG methylation in suicide victims with maltreatment history”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as McGowan et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“McGowan et al. reported reduced hippocampal NR3C1 expression in an all-male postmortem investigation comparing 12 suicide victims with a history of childhood abuse to 12 suicide victims without a history of childhood abuse as well as to 12 healthy control subjects (McGowan et al., 2009)”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as McGowan et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“in vitro patch methylation mimicking this epigenetic state resulted in decreased NGFI-A binding and correspondingly reduced NGFI-A-induced gene transcription (McGowan et al., 2009)”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as McGowan et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“↑ NR3C1 methylation in suicide victims with maltreatment history”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as McGowan et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“McGowan and colleagues found that a history of severe childhood abuse (ascertained with proxy-based interviews) was associated with increased NR3C1 methylation in the hippocampus.”
The cited source says what the claim attributes to it.
In the citing paper
“The findings concerning NR3C1 are of particular relevance given that they align with the animal studies and replicate the earlier observations with brain tissue.”
The cited source says what the claim attributes to it.
In the citing paper
“Increased methylation of the NR3C1 promoter and reduced glucocorticoid receptor expression have been observed in hippocampal tissue of suicide completers with histories of maltreatment (119, 120).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [119]
The cited source says what the claim attributes to it.
In the citing paper
“Other studies have also observed associations between childhood maltreatment and differences in DNAm in the brain, 58 blood, 59 , 60 and even gametes. 61”
From Epigenetics and depression (2019) · cites this paper as [58]
In the citing paper
“Maternal care in infancy contributes to epigenetic regulation of the glucocorticoid receptor in the hippocampus (Anacker et al., 2014; McGowan et al., 2009) as well as in peripheral immune cells (Miller et al., 2011; Tyrka et al., 2012).”
From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as McGowan et al., 2009
In the citing paper
“abused suicide victims had increased CpG methylation of the NR3C1 promoter, concomitant with a decrease in NR3C1 gene expression 126.”
From Resilience in mental health: linking psychological and neurobiological perspectives. (2013) · cites this paper as [126]
In the citing paper
“Embryonic development and early life are two major susceptibility windows during which epigenetic programming is sensitive to environmental influences, such as diet, temperature, environmental toxins, maternal behaviour or childhood abuse 137 .”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [137]
In the citing paper
“Hippocampal samples from individuals with a history of abuse or extreme neglect showed decreased hippocampal GR mRNA levels.”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [65]
In the citing paper
“Nevertheless, there is direct evidence for an association between childhood maltreatment and hippocampal GR expression.65”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [65]
In the citing paper
“We65,120 showed decreased hippocampal GR expression in samples from suicide completers with histories of childhood maltreatment compared with controls (sudden, involuntary fatalities).”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [65]
In the citing paper
“The exon 1F sequence is of particular interest as it is the homolog of the rat exon 17, is highly expressed in brain and contains an NGFI-A response element.65,121”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [65]
In the citing paper
“Suicide risk may be mediated by genetic and epigenetic effects of stress response genes (58-61).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [60]
In the citing paper
“Glucocorticoid receptors are subject to genetic effects via chaperone proteins like SKA1 and FKBP5 (58, 148, 149), as well as epigenetic changes (i.e., methylation) observed in response to maternal deprivation in rats (150) and in suicide decedents with a history of childhood adversity (60).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [60]
In the citing paper
“A milestone study confirmed what had been previously shown in animal models: human parental care impacts epigenetic regulation of hippocampal glucocorticoid receptor gene (NR3C1) expression [138].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [138]
In the citing paper
“Abnormal DNA methylation at specific genes has been observed in patients with neuropsychiatric disorders and in animal models of depression and anxiety.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [103]
In the citing paper
“In human post-mortem specimens, epigenetic differences were found in methylation of the neuron-specific NR3C1 promoter (GR1 F ) in the hippocampus between suicide victims with a history of childhood abuse and those who committed suicide but had no abuse history and non-suicide controls.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [103]
In the citing paper
“The authors reported lower levels of both glucocorticoid receptor mRNA and GR1 F splice variant mRNA but higher cytosine methylation of the GR1 F promoter in the group with abuse.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [103]
In the citing paper
“as compared to average reported increases for the same regions resulting from early-life stress of 95%32–34 and 135%29, 30, 47, respectively”
From Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice (2017) · cites this paper as [47]
In the citing paper
“adversity-related increases in methylation in this region are associated with decreased gene expression in human postmortem brain tissue (McGowan et al., 2009) and increased physiological stress responding in infants (Oberlander et al., 2008).”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as McGowan et al., 2009
In the citing paper
“The fact that the current data replicate previously demonstrated associations between child maltreatment and methylation of the GR gene”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as McGowan et al., 2009
In the citing paper
“Similar associations between early adversity and GR NR3C1 methylation have recently been demonstrated in humans who likely experienced severe stress or trauma. These samples have included brain tissue of deceased human adults who had committed suicide following a history of child abuse (McGowan et al., 2009), cord blood of infants with depressed mothers (Oberlander et al., 2008), white blood cells”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as McGowan et al., 2009
In the citing paper
“our results are consistent with previous research in adult humans demonstrating an association between child abuse and methylation differences, despite differences in sample characteristics”
From Associations Between Early Life Stress and Gene Methylation in Children (2015) · cites this paper as McGowan et al., 2009
In the citing paper
“Likewise the increased CpG methylation within the GR promotor is associated with a sluggish HPA stress response and is associated with poor maternal care in rodents and early life abuse in human suicide victims.”
From Neurobiological and Systemic Effects of Chronic Stress (2017) · cites this paper as [33]
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Metadata
- Authors
- McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., Turecki, G., & Meaney, M. J.
- Affiliations
- Douglas Mental Health University Institute (CA)
- McGill University (CA)
- Corresponding author
- Turecki, Gustavo
- Meaney, Michael J
- Venue
- Nature Neuroscience
- Published
- 2009-02-22
- Volume
- 12
- Issue
- 3
- Pages
- 342-348
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2944040
- OpenAlex
- W2148337554
- Cited by
- 3,531
- References
- 52
- Citations by year
- 2026: 112 · 2025: 100 · 2024: 108 · 2023: 143 · 2022: 123 · 2021: 146 · 2020: 248 · 2019: 213 · 2018: 209 · 2017: 197 · 2016: 274 · 2015: 270 · 2014: 308 · 2013: 260 · 2012: 278
- FWCI
- 103.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD051897)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- glucocorticoid receptor, NR3C1, childhood abuse, child neglect, suicide, epigenetic regulation, DNA methylation, hippocampus, hypothalamic-pituitary-adrenal axis, NGFI-A, promoter methylation, maternal care, postmortem brain
- MeSH terms
- Adult, Base Sequence, Cell Line, Female, Hippocampus, Humans, Male, Middle Aged, Molecular Sequence Data, Promoter Regions, Genetic, Receptors, Glucocorticoid, Suicide, DNA Methylation, Epigenesis, Genetic, Adult Survivors of Child Abuse, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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