Multigenerational epigenetic inheritance: One step forward, two generations back
Open accessAbstract
Modifications to DNA and histone proteins serve a critical regulatory role in the developing and adult brain, and over a decade of research has established the importance of these "epigenetic" modifications in a wide variety of brain functions across the lifespan. Epigenetic patterns orchestrate gene expression programs that establish the phenotypic diversity of various cellular classes in the central nervous system, play a key role in experience-dependent gene regulation in the adult brain, and are commonly implicated in neurodevelopmental, psychiatric, and neurodegenerative disease states. In addition to these established roles, emerging evidence indicates that epigenetic information can potentially be transmitted to offspring, giving rise to inter- and trans-generational epigenetic inheritance phenotypes. However, our understanding of the cellular events that participate in this information transfer is incomplete, and the ability of this transfer to overcome complete epigenetic reprogramming during embryonic development is highly controversial. This review explores the existing literature on multigenerational epigenetic mechanisms in the central nervous system. First, we focus on the cellular mechanisms that may perpetuate or counteract this type of information transfer, and consider how epigenetic modification in germline and somatic cells regulate important aspects of cellular and organismal development. Next, we review the potential phenotypes resulting from ancestral experiences that impact gene regulatory modifications, including how these changes may give rise to unique metabolic phenotypes. Finally, we discuss several caveats and technical limitations that influence multigenerational epigenetic effects. We argue that studies reporting multigenerational epigenetic changes impacting the central nervous system must be interpreted with caution, and provide suggestions for how epigenetic information transfer can be mechanistically disentangled from genetic and environmental influences on brain function.
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Alterations across stress-regulatory, neurodevelopmental, immune, and metabolic systems have been linked to increased vulnerability to PTSD, depression, anxiety, suicide, and chronic medical conditions, including metabolic syndrome and immune dysregulation.
“Alterations across stress-regulatory, neurodevelopmental, immune, and metabolic systems have been linked to increased vulnerability to post-traumatic stress disorder (PTSD), depression, anxiety, suicide, and chronic medical conditions, including metabolic syndrome and immune dysregulation (12).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [12]
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Kac, E., Qi, Q., & Ryznar, R. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1769422 · Cited by 1 · see citing works
“Alterations across stress-regulatory, neurodevelopmental, immune, and metabolic systems have been linked to increased vulnerability to post-traumatic stress disorder (PTSD), depression, anxiety, suicide, and chronic medical conditions, including metabolic syndrome and immune dysregulation (12).”
- Authors
- Tuscher, J. J., & Day, J. J.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Tuscher, Jennifer J.
- Day, Jeremy J.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 132
- Pages
- 104591
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2971065276
- Cited by
- 63
- References
- 22
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 15 · 2021: 10 · 2020: 5
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Foundation for the National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- transgenerational epigenetic inheritance, DNA methylation, histone modifications, epigenetic reprogramming, metabolic phenotypes, brain development, central nervous system development, gene regulatory mechanisms
- MeSH terms
- Animals, Brain, Gene Expression Regulation, Humans, Epigenesis, Genetic, Neurogenesis
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