Genome-wide epigenetic regulation by early-life trauma
Open accessAbstract
CONTEXT: Our genome adapts to environmental influences, in part through epigenetic mechanisms, including DNA methylation. Variations in the quality of the early environment are associated with alterations in DNA methylation in rodents, and recent data suggest similar processes in humans in response to early-life adversity. OBJECTIVE: To determine genome-wide DNA methylation alterations induced by early-life trauma. DESIGN: Genome-wide study of promoter methylation in individuals with severe abuse during childhood. PATIENTS, SETTING, AND MAIN OUTCOME MEASURES: Promoter DNA methylation levels were profiled using methylated DNA immunoprecipitation followed by microarray hybridization in hippocampal tissue from 41 French-Canadian men (25 with a history of severe childhood abuse and 16 control subjects). Methylation profiles were compared with corresponding genome-wide gene expression profiles obtained by messenger RNA microarrays. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Functional consequences of site-specific promoter methylation were assessed by luciferase assays. RESULTS: We identified 362 differentially methylated promoters in individuals with a history of abuse compared with controls. Among these promoters, 248 showed hypermethylation and 114 demonstrated hypomethylation. Validation and site-specific quantification of DNA methylation in the 5 most hypermethylated gene promoters indicated that methylation differences occurred mainly in the neuronal cellular fraction. Genes involved in cellular/neuronal plasticity were among the most significantly differentially methylated, and, among these, Alsin (ALS2) was the most significant finding. Methylated ALS2 constructs mimicking the methylation state in samples from abused suicide completers showed decreased promoter transcriptional activity associated with decreased hippocampal expression of ALS2 variants. CONCLUSION: Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.
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Labonte and colleagues reported that in hippocampal tissues derived from those who had died by suicide, comparing those with and without a history of childhood abuse, there were 362 differentially methylated promoter sites; among these, 248 sites were hypermethylated and 114 were hypomethylated.
“For example, Labonte and colleagues reported that in hippocampal tissues derived from those who had died by suicide, comparing those with and without a history of childhood abuse, there were 362 differentially methylated promoter sites. Among these, 248 sites were hypermethylated and 114 were hypomethylated (102).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [102]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA genome-wide study of hippocampal tissue from 41 adult males found 362 differentially methylated gene promoter regions in individuals (n=25) who had experienced child abuse and completed suicide compared with psychiatrically healthy controls (n=16).
“A genome-wide study of hippocampal tissue from 41 adult males found 362 differentially methylated gene promoter regions in individuals (n=25) who had experienced child abuse and completed suicide, compared with the psychiatrically healthy controls (n=16).”
From Epigenetics and depression (2019) · cites this paper as [57]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn depression, altered chromatin accessibility has been observed at BDNF, GAD1, NR3C1 in response to stress.
“In depression, altered chromatin accessibility have been observed at BDNF, GAD1, NR3C1 in response to stress”
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 [43]
The passage labeled Abstract (page unavailable) describes stress-related promoter hypermethylation involving BDNF, GAD1, and glucocorticoid-receptor variants, including methylation that constrains transcription-factor binding. It does not establish altered chromatin accessibility at all three genes in people with depression: the BDNF and GAD1 examples concern stressed rats, while the human example concerns suicide completers with childhood abuse. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn suicide studies, individuals with a history of suicide attempts or ideation that have been exposed to trauma have increased SLC6A4 methylation.
“In suicide studies, individuals with a history of suicide attempts or ideation that have been exposed to trauma have increased SLC6A4 methylation”
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 [43]
The sample-selection section describes people who died by suicide, including a group with severe early-life abuse. The ALS2 promoter results report increased methylation in that abused group. The cited paper does not establish the claimed increase in SLC6A4 methylation or study people identified by a history of suicide attempts or ideation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThese DMRs were most pronounced in the neuronal fraction of the brain tissue and were enriched in genes involved in neuroplasticity.
“These DMRs were most pronounced in the neuronal fraction of the brain tissue, and consistent with the findings in animal studies mentioned above, were enriched in genes involved in neuroplasticity. 57”
From Epigenetics and depression (2019) · cites this paper as [57]
The GENOME-WIDE PROMOTER METHYLATION DIFFERENCES section reports that four of five promoters tested showed significant methylation differences specific to the neuronal fraction; it does not establish this for all identified DMRs. The same section reports significant enrichment of genes associated with neuronal plasticity among differentially methylated genes. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Reduced GR mRNA expression is mediated by epigenetic modifications.
“Reduced levels of GR mRNA expression are seen in all hippocampal subfields [73,102] , which may be central to impaired HPA inhibitory regulation and mediated by epigenetic modifications [104] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [104]
In post-mortem brain tissue from suicide completers with a history of abuse, NR3C1 methylation is increased.
“In studies of post-mortem brain tissue from suicide completers with a history of abuse, NR3C1 methylation is increased”
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 [43]
Subsequent studies have confirmed similar NR3C1 methylation patterns in peripheral blood, suggesting a promising but not yet clinically validated peripheral biomarker of central stress dysregulation.
“Subsequent studies have confirmed similar patterns in peripheral blood, suggesting a promising but not yet clinically validated peripheral biomarker of central stress dysregulation (56, 57).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [56]
The introductory passage describes NR3C1-related methylation in hippocampal tissue, and the Conclusions describe this study’s genome-wide analysis of hippocampal tissue. Neither passage, nor the additional passages searched for peripheral blood and biomarkers, addresses whether similar patterns were confirmed in blood or could serve as a peripheral biomarker. (LLM, conf=0.76)
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ALS2/Alsin Regulates Rac-PAK Signaling and Neurite Outgrowth
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Self-citationALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth
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β-Catenin Promoter ChIP-Chip Reveals Potential Schizophrenia and Bipolar Disorder Gene Network
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Research works printed but not linked: 1
- Bagot RC, Meaney MJ. Epigenetics and the biological basis of geneϫenvironment interactions. J Am Acad Child Adolesc Psychiatry. 2010;49(8):752-771.
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The Biological Effects of Childhood Trauma
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Epigenetics of Stress-Related Psychiatric Disorders and Gene × Environment Interactions
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Epigenetic basis of mental illness
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“Among these, 248 sites were hypermethylated and 114 were hypomethylated (102).”
BackgroundThe molecular bases of the suicidal brain
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“Subsequent studies have confirmed similar patterns in peripheral blood, suggesting a promising but not yet clinically validated peripheral biomarker of central stress dysregulation (56, 57).”
- Authors
- Labonté, B., Suderman, M., Maussion, G., Navaro, L., Yerko, V., Mahar, I., Bureau, A., Mechawar, N., Szyf, M., Meaney, M. J., & Turecki, G.
- Affiliations
- Douglas Mental Health University Institute (CA)
- Consejo Superior de Investigaciones Científicas (ES)
- McGill University (CA)
- Johns Hopkins University (US)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Turecki, Gustavo
- ORCID
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-07-01
- Volume
- 69
- Issue
- 7
- Pages
- 722-31
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC4991944
- OpenAlex
- W2096799018
- Cited by
- 488
- References
- 86
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 15 · 2023: 27 · 2022: 20 · 2021: 37 · 2020: 73 · 2019: 33 · 2018: 44 · 2017: 27 · 2016: 39 · 2015: 39 · 2014: 61 · 2013: 44 · 2012: 5
- FWCI
- 19.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (84291_1, MOP84291)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Keywords
- early trauma, childhood abuse, DNA methylation, promoter methylation, epigenetic regulation, hippocampus, neuroplasticity, ALS2, alsin, suicide, gene expression
- MeSH terms
- Adult, Child, Child Abuse, Female, Hippocampus, Humans, Life Change Events, Male, Neurons, Promoter Regions, Genetic, Genome, DNA Methylation, Epigenesis, Genetic
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