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Cited by 75Epigenetics and DNA MethylationStress Responses and CortisolChild Abuse and Trauma

Cell-type-specific epigenetic effects of early life stress on the brain

Open access
Rahman, Mouly F., McGowan, Patrick O.·2022·Translational Psychiatry
DOI 10.1038/s41398-022-02076-9PMC PMC9365848
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Abstract

Early life stress (ELS) induces long-term phenotypic adaptations that contribute to increased vulnerability to a host of neuropsychiatric disorders. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, are a proposed link between environmental stressors, alterations in gene expression, and phenotypes. Epigenetic modifications play a primary role in shaping functional differences between cell types and can be modified by environmental perturbations, especially in early development. Together with contributions from genetic variation, epigenetic mechanisms orchestrate patterns of gene expression within specific cell types that contribute to phenotypic variation between individuals. To date, many studies have provided insights into epigenetic changes resulting from ELS. However, most of these studies have examined heterogenous brain tissue, despite evidence of cell-type-specific epigenetic modifications in phenotypes associated with ELS. In this review, we focus on rodent and human studies that have examined epigenetic modifications induced by ELS in select cell types isolated from the brain or associated with genes that have cell-type-restricted expression in neurons, microglia, astrocytes, and oligodendrocytes. Although significant challenges remain, future studies using these approaches can enable important mechanistic insight into the role of epigenetic variation in the effects of ELS on brain function.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that early life stress (ELS) can induce persistent, cell-type-specific epigenetic reprogramming in the brain, but most existing evidence comes from heterogeneous tissue and cannot identify the driving cell types. It surveys rodent and human studies using cell-type-enriched isolates or cell-type-restricted genes in neurons, microglia, astrocytes, and oligodendrocytes, and outlines technical and interpretive challenges for future work.

Key findings

  • In neurons, adverse caregiving from PND1–7 increased *Bdnf* exon IV DNA methylation across 12 CpG sites in medial prefrontal cortex neurons of adult female but not male rats; neonatal maternal separation increased retinoic acid receptor promoter CpG island methylation in adult dentate gyrus neural precursor cells from male rats.
  • In microglia, maternal allergic asthma in adolescent female mice produced whole-genome bisulfite sequencing differentially methylated regions enriched for cytokine signaling pathways; neonatal alcohol increased histone H3K9 acetylation at *Tnfa* and *Il6* promoters in mediobasal hypothalamus microglia at PND6 and PND90; maternal separation plus handling reduced *Il10* CpG island methylation in nucleus accumbens microglia of adult male rats, a change absent in whole tissue.
  • In astrocytes and oligodendrocytes, maternal separation reduced *Gfap* promoter CpG methylation in frontal cortex of adolescent male rats; human suicide completers with childhood abuse showed decreased *LINGO3* and *POU3F1* CpG methylation in anterior cingulate cortex oligodendrocytes; maternal gestational psychosocial stress increased whole-brain miR-219 in male rats.
  • The review states that only one human study was found within its scope, that cell-specific glial evidence is very limited, and that non-coding RNA measurement in this context has been limited to miRNA.

Methods

  • Narrative review of rodent and human studies examining ELS-induced epigenetic modifications in cell-type-enriched brain isolates or in genes with cell-type-restricted expression in neurons, microglia, astrocytes, and oligodendrocytes.
  • Inclusion criteria: inflammation-based or psychosocial ELS at prenatal, perinatal, or neonatal stages; female and male offspring from PND1 to adulthood; human and rodent studies; pre-conceptional parental or transgenerational stress was excluded. Table 1 summarizes the reviewed articles.
  • Main analysis is qualitative synthesis of findings by cell type, plus discussion of limitations of heterogeneous tissue, cell-type-specific approaches, and future methods including epigenetic editing.

Limitations

  • Stated by the paper: most prior studies used heterogeneous brain tissue, which can mask cell-type-specific epigenetic marks or reflect cell-type proportion differences; cell-specific glial evidence is very limited; ncRNA work is limited to miRNA; cell-type definitions remain contested; epigenetic marks may not map simply to steady-state gene expression or behavior; causal inference requires in vivo epigenetic editing, and CRISPR/dCas9 approaches can have off-target effects.
  • Stated by the paper: animal models only approximate human ELS, rodents are immunologically naïve, and forms of psychosocial ELS and human resiliency factors are difficult to model.
  • Evident from the text: this is a review rather than primary data; only one human study fell within scope; many reviewed findings rely on whole-brain tissue or cell-type-enriched expression rather than purified isolates, and sex/age coverage is uneven, with some studies combining sexes or leaving sex undeclared.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41398-022-02076-9

Cites

165 of 165 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    It is not guaranteed that similar epigenetic modifications will exist within defined cell types, even within a brain region.

    “Thus, it is not guaranteed that similar epigenetic modifications will exist within defined cell types, even within a brain region.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Differences in the epigenetic mark of a gene expressed in multiple cell types may be difficult to interpret if the function of the gene varies between cell types.

    “First, differences in the epigenetic mark (and expression levels) of a particular gene that is expressed in multiple cell types may be difficult to interpret if the function of a given gene varies between cell types.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Retinoic acid receptor promoter CpG island methylation is increased in adult neural precursor cells isolated from the dentate gyrus of adult male rats that underwent neonatal maternal separation.

    “Retinoic acid receptor, also critical to neurodevelopment, specifically neural differentiation, was found in another study to have increased promoter CpG island methylation in adult neural precursor cells isolated from the dentate gyrus of adult male rats (females unexamined) that underwent neonatal maternal separation (MS) [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Boku S, Toda H, Nakagawa S, Kato A, Inoue T, Koyama T, et al. Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter. Biol Psychiatry. 2015;77:335–44. source

      Not checked in the free run.

  • Interpretationreasoning

    Differences in the epigenetic modifications of a gene expressed in multiple cell types can be masked by background noise resulting from constitutive epigenetic modifications related to cell type-specific functions.

    “Second, differences in the epigenetic modifications of a gene expressed in multiple cell types can be masked by ‘background noise’ resulting from constitutive epigenetic modifications related to cell type-specific functions.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Converging evidence supports the role of epigenetic modifications as mediators of the impact of ELS on long-term neurobiological alterations.

    “Converging evidence supports the role of epigenetic modifications as mediators of the impact of ELS on long-term neurobiological alterations.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 10
  • May combine two claims. 9

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tools used for cell-type-specific epigenetic editing include zinc-finger proteins, which can be fused with histone modifiers and target specific DNA sequences, and transcriptional activator-like effectors (TALEs), DNA binding proteins from bacteria that can be targeted to regulate gene transcription.

    “Tools used for cell-type-specific epigenetic editing include zinc-finger proteins, which can be fused with histone modifiers and target specific DNA sequences, and transcriptional activator-like effectors (TALEs), DNA binding proteins from bacteria that can be targeted to regulate gene transcription (see review [156]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Yim YY, Teague CD, Nestler EJ. In vivo locus-specific editing of the neuroepigenome. Nat Rev Neurosci. 2020;21:471–84. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the PFC of female rats exposed to neonatal caregiver maltreatment, Bdnf exon IV methylation was reduced at adolescence compared to normal care controls, increased at adulthood, and did not differ at infancy.

    “one study found that in the PFC of female rats exposed to neonatal caregiver maltreatment, there was reduced Bdnf exon IV methylation at adolescence compared to normal care controls, but an increase at adulthood, and no differences at infancy [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Blaze J, Scheuing L, Roth TL. Differential methylation of genes in the medial prefrontal cortex of developing and adult rats following exposure to maltreatment or nurturing care during infancy. Developmental Neurosci. 2013;35:306–16. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The study of cell-type-specific epigenetic modifications requires sophisticated technical approaches.

    “The study of cell-type-specific epigenetic modifications requires sophisticated technical approaches.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neonatal alcohol exposure increased histone acetylation at Tnfa and Il6 promoters in hypothalamic microglia in adult rats at baseline and post-LPS challenge, but increased transcript abundance of microglial mRNA of these genes only occurred in the post-LPS condition and not at baseline.

    “neonatal alcohol exposure was found to increase histone acetylation at Tnfa and Il6 promoters in hypothalamic microglia in adult rats at baseline and post-LPS challenge, however increased transcript abundance of microglial mRNA of these genes only occurred in the post-LPS condition and not at baseline [130].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Chastain LG, Franklin T, Gangisetty O, Cabrera MA, Mukherjee S, Shrivastava P, et al. Early life alcohol exposure primes hypothalamic microglia to later-life hypersensitivity to immune stress: possible epigenetic mechanism. Neuropsychopharmacology. 2019;44:1579–88. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Measuring epigenetic changes in multiple cell types is needed to assess the specificity of such modifications.

    “While measuring epigenetic changes in one cell type may provide information regarding mechanisms associated with its biological function, measuring them in multiple cell types would be needed to assess the specificity of such modifications.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The use of CRISPR, fusion and DNA binding proteins in combination with cell-specific analysis may help delineate the epigenetic mechanisms through which ELS leads to long-term perturbations on behavior, and improve therapeutic approaches for a variety of neuropsychiatric and neurodevelopmental disorders.

    “However, the use of CRISPR, fusion and DNA binding proteins in combination with cell-specific analysis may help delineate the epigenetic mechanisms through which ELS leads to long-term perturbations on behavior, and improve therapeutic approaches for a variety of neuropsychiatric and neurodevelopmental disorders.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Early life stress leads to long-term perturbations on behavior through epigenetic mechanisms.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Epigenetic changes found in a certain cell type do not necessarily mean that similar changes are absent in other cell types.

    “Of course, epigenetic changes found in a certain cell type do not necessarily mean that similar changes are absent in other cell types.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Isolating particular cells involved in a neural circuit or biological pathway may be more informative in delineating epigenetic changes contributing to particular phenotypes.

    “As such, isolating particular cells involved in a ‘neural circuit’ or biological pathway may be more informative in delineating epigenetic changes contributing to particular phenotypes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Early life stress (ELS) induces long-term phenotypic adaptations that contribute to increased vulnerability to a host of neuropsychiatric disorders.

    “Early life stress (ELS) induces long-term phenotypic adaptations that contribute to increased vulnerability to a host of neuropsychiatric disorders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Together with contributions from genetic variation, epigenetic mechanisms orchestrate patterns of gene expression within specific cell types that contribute to phenotypic variation between individuals.

    “Together with contributions from genetic variation, epigenetic mechanisms orchestrate patterns of gene expression within specific cell types that contribute to phenotypic variation between individuals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In adult male rats born to dams with gestational psychosocial stress, miR-133b levels are increased in the hippocampus and decreased in the PFC.

    “In adult male rats born to dams with gestational psychosocial stress, miR-133b was found to have increased levels in the hippocampus (HPC) and decreased levels in the PFC [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Monteleone MC, Adrover E, Pallarés ME, Antonelli MC, Frasch AC, Brocco MA. Prenatal stress changes the glycoprotein gpm6a gene expression and induces epigenetic changes in rat offspring brain. Epigenetics. 2014;9:152–60. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In adult male rats, maternal separation alone or combined with chronic unpredictable stress increases miR-326 in the nucleus accumbens and reduces it in the striatum.

    “MiR-326, which has neuron-enriched expression in the neocortex [105, 114, 115] and targets the dopamine D2 receptor [116] was found to be increased in the nucleus accumbens (NAc) and reduced in the striatum of adult male rats exposed to MS alone, and MS combined with maternal chronic unpredictable stress [117].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Zhang Y, Wang Y, Wang L, Bai M, Zhang X, Zhu X. Dopamine receptor D2 and associated microRNAs are involved in stress susceptibility and resistance to escitalopram treatment. Int J Neuropsychopharmacol. 2015;18:1–10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Maternal separation plus handling reduces CpG island methylation of Il10 in microglia isolated from the NAc of adult male rats, a change absent in whole tissue.

    “Similar to these findings that suggest there is an increased pro-inflammatory phenotype in offspring exposed to ELS, the anti-inflammatory cytokine Il10 showed reduced levels of CpG island methylation in microglia isolated from the NAc of adult male rats that underwent MS as well as handling, a change that was absent in whole tissue from the NAc [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Schwarz JM, Hutchinson MR, Bilbo SD. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J Neurosci. 2011;31:17835–47. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Epigenetic modifications play a primary role in shaping functional differences between cell types and can be modified by environmental perturbations, especially in early development.

    “Epigenetic modifications play a primary role in shaping functional differences between cell types and can be modified by environmental perturbations, especially in early development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Epigenetic editing with CRISPR/dCas9 can involve off-target effects.

    “Epigenetic editing with CRISPR/dCas9 is not without its limitations, as it can involve off-target effects [155, 159].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Hamilton PJ, Lim CJ, Nestler EJ, Heller EA. Neuroepigenetic editing. Methods Mol Biol. 2018;1767:113. source

      Not checked in the free run.

    • cites [159] Zhang XH, Tee LY, Wang XG, Huang QS, Yang SH. Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther - Nucleic Acids. 2015;4:e264. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Most studies of epigenetic changes resulting from ELS have examined heterogeneous brain tissue, despite evidence of cell-type-specific epigenetic modifications in phenotypes associated with ELS.

    “However, most of these studies have examined heterogenous brain tissue, despite evidence of cell-type-specific epigenetic modifications in phenotypes associated with ELS.”
    Quote in the paperSubstantial claim
16 of 16

  • The paper relies on this without support.

    Early life stress leads to long-term perturbations on behavior through epigenetic mechanisms.

    “the epigenetic mechanisms through which ELS leads to long-term perturbations on behavior”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Studies demonstrate that epigenetic editing interventions can alleviate symptoms of MDD, anxiety, and PTSD while enhancing cognitive resilience.

    “These therapies focus on reversing stress-induced gene silencing, and studies demonstrate that such interventions can alleviate symptoms of MDD, anxiety, PTSD, while enhancing cognitive resilience (124).”

    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 [124]

    The Challenges and outlook section (page unavailable) reports that targeted epigenetic modification produced stress susceptibility or resilience in mice, and discusses possible therapeutic approaches. It does not report that epigenetic editing alleviates MDD, anxiety, or PTSD symptoms, or enhances cognitive resilience. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Abused suicide victims show decreased levels of glucocorticoid receptor mRNA and increased methylation of the receptor promoter compared to non-abused suicide victims.

    “Abused suicide victims show decreased levels of glucocorticoid receptor mRNA and an increased methylation of the receptor promoter compared to non-abused suicide victims [9,59].”

    From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [59]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Striatal miR-326 result attributed to MS alone

    Minor

    The text says reduced striatal miR-326 occurred after maternal separation (MS) alone and MS combined with chronic unpredictable stress (CUS). Table 1 restricts the striatal reduction to CUS and MS+CUS, excluding MS alone.

  • miR-323 offspring age differs between text and table

    Minor

    The text describes the rats in the miR-323 maternal-stress study as adults, but Table 1 lists their age as PND0.

2 of 2

Cites

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Related

Authors
Rahman, M. F., & McGowan, P. O.
Affiliations
University of Toronto (CA)
Corresponding author
McGowan, Patrick O.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-08-10
Volume
12
Issue
1
Pages
326-326
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-022-02076-9
PMC
PMC9365848
OpenAlex
W4291020981
Semantic Scholar
666b66ed40bbe8d610cad4fd5a5ae75f5b061970
Cited by
75
References
165
Citations by year
2026: 15 · 2025: 21 · 2024: 22 · 2023: 16 · 2022: 1
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Natural Sciences and Engineering Research Council of Canada
  • Ontario Graduate Scholarship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Keywords
early life stress, epigenetic modifications, cell-type-specific epigenetics, DNA methylation, histone modifications, non-coding RNA, brain development, neurons, microglia, astrocytes, oligodendrocytes, neuropsychiatric disorders, gene expression, rodent models, human subjects research
MeSH terms
Adverse Childhood Experiences, Animals, Brain, Humans, Stress, Psychological, DNA Methylation, Epigenesis, Genetic, Epigenomics

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