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Cited by 195Epigenetics and DNA MethylationSperm and Testicular FunctionGenetic Syndromes and Imprinting

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Open access
Gapp, K., van Steenwyk, G., Germain, P. L., Matsushima, W., Rudolph, K. L. M., Manuella, F., Roszkowski, M., Vernaz, G. +4 more·2020·Molecular Psychiatry
DOI 10.1038/s41380-018-0271-6PMC PMC7473836

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Abstract

Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells. Initial evidence suggested that sperm RNA is causally linked to the transmission of symptoms induced by traumatic experiences. Here, we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioural despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.

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  • Animal models have demonstrated epigenetic remodeling of stress-related genes and histone acetylation patterns in brain regions involved in emotional regulation following early-life stress.

    “Animal models have also demonstrated epigenetic remodeling of stress-related genes and histone acetylation patterns in brain regions involved in emotional regulation following early-life stress (116, 117).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [117]

    The Discussion (page not provided) says that transposable-element expression in the brain responds to acute and chronic stress and that glucocorticoid-mediated epigenetic remodelling has been suggested. It does not establish remodelling of stress-related genes or histone acetylation patterns in emotion-regulating brain regions following early-life stress; the cited histone studies in the References concern methylation, not acetylation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Evidence suggests involvement of stress-response regulation, neurodevelopmental and emotional processing pathways, and epigenetic remodeling processes in shaping intergenerational outcomes.

    “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 [117]

    The Results sections on sperm RNA and offspring behaviour report that postnatal trauma alters sperm RNA and that injected RNA fractions reproduce some behavioural effects in offspring. The Discussion proposes a possible role for stress-responsive transposable elements and epigenetic remodelling. Our copy does not establish neurodevelopmental or emotional-processing pathways, or offspring stress-response regulation, as mechanisms shaping those outcomes. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Childhood maltreatment, including abuse and neglect, represents a sustained early-life stressor associated with long-term biological and behavioral changes across generations.

    “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 [117]

    The Introduction (page unavailable) says early-life traumatic stress can have lasting behavioral and metabolic effects across generations. However, the Methods describe a mouse model involving maternal separation and stress from postnatal days 1–14, not childhood abuse or neglect in humans; the paper does not establish the claim for childhood maltreatment generally. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Behavioral and metabolic phenotypes were observed in subsequent generations, and injection of sperm RNA from exposed males into naive zygotes reproduced several of these features.

    “Behavioral and metabolic phenotypes were observed in subsequent generations, and injection of sperm RNA from exposed males into naive zygotes reproduced several of these features (116, 117).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [117]

  • In animal studies using the maternal separation with unpredictable stress (MSUS) paradigm, exposed males demonstrated alterations in sperm small and long noncoding RNAs.

    “In animal studies using the maternal separation with unpredictable stress (MSUS) paradigm, exposed males demonstrated alterations in sperm small and long noncoding RNAs (116, 117).”

    From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [117]

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Authors
Gapp, K., van Steenwyk, G., Germain, P. L., Matsushima, W., Rudolph, K. L. M., Manuella, F., Roszkowski, M., Vernaz, G., Ghosh, T., Pelczar, P., Mansuy, I. M., & Miska, E. A.
Affiliations
  • University of Cambridge (GB)
  • University of Zurich (CH)
  • University of Basel (CH)
Corresponding author
  • Mansuy, I. M.
  • Miska, E. A.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2018-10-30
Volume
25
Issue
9
Pages
2162-2174
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-018-0271-6
PMC
PMC7473836
OpenAlex
W2885557879
Cited by
195
References
9
Citations by year
2026: 15 · 2025: 22 · 2024: 23 · 2023: 33 · 2022: 29 · 2021: 29 · 2020: 25 · 2019: 19
FWCI
6.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Apollo (cc-by)
  • ETH Zürich Research Collection (cc-by)
Funders
  • National Science Foundation
  • Novartis Foundation
  • Wellcome Trust (104640/Z/14/Z, 092096/Z/10/Z, 203144, 203144/A/16/Z, 203144/Z/16/Z)
  • Cancer Research UK (A18583, 092096/Z/10/Z, C6946/A24843, C13474/A18583, C6946/A14492, C13474/A18583, C13474, C6946 /A14492, 092096, C6946, A24843, 18583, A14492)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (159096, 167698)
  • Österreichischen Akademie der Wissenschaften
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
Keywords
epigenetic inheritance, germ cells, small RNA, dietary intake, risk-taking, behavioural despair, body weight, fertilisation (biology)
MeSH terms
Humans, Male, RNA, Spermatozoa, DNA Methylation, Epigenesis, Genetic, Epigenomics

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