Multigenerational epigenetic adaptation of the hepatic wound-healing response
Open accessAbstract
We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F1 and F2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor γ (PPAR-γ) and lower expression of the profibrogenic factor transforming growth factor β1 (TGF-β1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-γ chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to naive rats and similar modifications were induced in mesenchymal stem cells exposed to conditioned media from cultured rat or human myofibroblasts. Thus, it is probable that a myofibroblast-secreted soluble factor stimulates heritable epigenetic signatures in sperm so that the resulting offspring better adapt to future fibrogenic hepatic insults. Adding possible relevance to humans, we found that people with mild liver fibrosis have hypomethylation of the PPARG promoter compared to others with severe fibrosis.
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Almost all experimental mouse models and the few observations in humans concern deleterious traits (congenital malformations, anxiety, glucose intolerance, obesity, cardiovascular diseases, cancer and premature death); an exception appears to be hepatic wound healing.
“Almost all of the experimental mouse models and the few observations in humans concern deleterious traits (congenital malformations, anxiety, glucose intolerance, obesity, cardiovascular diseases, cancer and premature death); an exception appears to be hepatic wound healing21.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [21]
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- Authors
- Zeybel, M., Hardy, T., Wong, Y. K., Mathers, J. C., Fox, C. R., Gackowska, A., Oakley, F., Burt, A. D., Wilson, C. L., Anstee, Q. M., Barter, M. J., Masson, S., Elsharkawy, A. M., Mann, D. A., & Mann, J.
- Affiliations
- Newcastle University (GB)
- Corresponding author
- Mann, Derek A
- Mann, Jelena
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-09
- Volume
- 18
- Issue
- 9
- Pages
- 1369-1377
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3489975
- OpenAlex
- W2123735783
- Cited by
- 279
- References
- 59
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 11 · 2023: 15 · 2022: 13 · 2021: 13 · 2020: 29 · 2019: 28 · 2018: 20 · 2017: 25 · 2016: 26 · 2015: 24 · 2014: 28 · 2013: 28 · 2012: 7
- FWCI
- 17.62
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-10-05)
- Open access
- green
- europepmc.org
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (WT074472MA, WT086755MA)
- National Institute for Health and Care Research (ACF-2010-01-007)
- Biotechnology and Biological Sciences Research Council
- National Institute on Alcohol Abuse and Alcoholism (U01AA018663, R21AA016682)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- epigenetic inheritance, sperm chromatin, liver fibrosis, myofibroblasts, PPARγ, TGF-β1, DNA methylation, histone acetylation, H2A.Z, H3K27me3, serum transfer, mesenchymal stem cells
- MeSH terms
- Acetylation, Actins, Adaptation, Biological, Animals, Histones, Humans, Immunohistochemistry, Liver Diseases, Male, Spermatozoa, Wound Healing, Blotting, Western, DNA Methylation, PPAR gamma, Rats, Transforming Growth Factor beta1, Myofibroblasts, Mesenchymal Stem Cells, Real-Time Polymerase Chain Reaction
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