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Multigenerational epigenetic adaptation of the hepatic wound-healing response

Lookup NU author(s): Dr Mujdat Zeybel, Dr Timothy Hardy, Frances Wong, Professor John Mathers, Christopher Fox, Dr Agata Page, Professor Fiona Oakley, Professor Alastair Burt, Dr Caroline Wilson, Professor Quentin Anstee, Dr Matthew Barter, Dr Steven Masson, Dr Ahmed Elsharkawy, Professor Derek Mann, Professor Jelena Mann

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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 F-1 and F-2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) and lower expression of the profibrogenic factor transforming growth factor beta 1 (TGF-beta 1) 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-gamma 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.


Publication metadata

Author(s): Zeybel M, Hardy T, Wong YK, Mathers JC, Fox CR, Gackowska A, Oakley F, Burt AD, Wilson CL, Anstee QM, Barter MJ, Masson S, Elsharkawy AM, Mann DA, Mann J

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2012

Volume: 18

Issue: 9

Pages: 1369-U110

Print publication date: 02/09/2012

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nm.2893

DOI: 10.1038/nm.2893


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