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Multigenerational epigenetic adaptation of the hepatic wound-healing response

Nature Medicine volume 18, pages 1369–1377 (2012)Cite this article

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A Corrigendum to this article was published on 05 October 2012

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Abstract

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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Figure 1: The presence of liver injury in male ancestors reduces liver fibrogenesis in F2-generation male offspring.
Figure 2: Paternally transmitted adaptation of the fibrogenic response in chronic injury is mediated by a low number of α-SMA–positive myofibroblasts in the liver.
Figure 3: Protected rats have altered expression of profibrogenic and antifibrogenic genes in their livers.
Figure 4: The fibrogenic response that is influenced by ancestral injury is limited to the liver.
Figure 5: Altered expression of profibrogenic and antifibrogenic genes in the livers of protected rats is underpinned by differences in DNA methylation.
Figure 6: Extrahepatic transmission of epigenetic modifications and evidence for modifications in DNA methylation at fibrogenic regulator genes that are associated with the progression of liver disease in humans.

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  • 05 October 2012

     In the version of this article initially published, in Figure 6f the left-hand graph was an inadvertent duplication of the right-hand graph. The error does not alter the overall conclusions of the paper. The figure has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. Cheshire for technical assistance and N. Perkins for helpful suggestions with writing the manuscript, M. Bashton for bioinformatic support with microarray analysis and R. Kendall for assistance with rat studies. We also thank J. Kirby and J. Brain for their help with obtaining ethical approval for the retrospective patient study. This work was supported by grants from US National Institutes of Health National Institute of Alcohol Abuse and Alcoholism (to J.M. and D.A.M.) grant numbers 1U01AA018663-01 and R21AA016682; Wellcome Trust grant numbers WT086755MA (to D.A.M.) and WT074472MA (to A.M.E.) and Newcastle Biomedical Research Centre and National Institute for Health Research (to J.M.). The Centre for Brain Ageing and Vitality is funded through the Lifelong Health and Wellbeing cross council initiative by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, the Engineering and Physical Sciences Research Council and the Economic and Social Research Council (to J.C.M.) and the Turkish Association For The Study Of The Liver (to M.Z.).

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  1. Derek A Mann and Jelena Mann: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Müjdat Zeybel, Timothy Hardy, Christopher R Fox, Agata Gackowska, Fiona Oakley, Alastair D Burt, Caroline L Wilson, Quentin M Anstee, Matt J Barter, Steven Masson, Ahmed M Elsharkawy, Derek A Mann & Jelena Mann

  2. Human Nutrition Research Centre, Centre for Brain Ageing and Vitality, Institute for Ageing and Health Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK

    Yi K Wong & John C Mathers

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Contributions

M.Z. performed the majority of the laboratory-based experiments and the related data analyses. J.M., T.H., Y.K.W., J.C.M., A.G. and C.L.W. performed a portion of the laboratory experiments and the related data analyses. C.R.F. carried out the surgery and all the in vivo experiments relating to unilateral ureteral obstruction. M.J.B. obtained, cultured and phenotyped human mesenchymal stem cells. S.M. and Q.M.A. obtained archival human liver biopsy tissue and divided patients into groups based on their case history and disease severity. A.D.B. carried out all morphological analyses of tissue sections and scoring of patient liver pathology. A.M.E., F.O. and J.M. carried out all in vivo experiments. J.M. and D.A.M. designed the experiments and wrote the manuscript. All authors discussed the paper and commented on the manuscript.

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Correspondence to Derek A Mann or Jelena Mann.

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Zeybel, M., Hardy, T., Wong, Y. et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med 18, 1369–1377 (2012). https://doi.org/10.1038/nm.2893

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