Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/82592
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Type: Journal article
Title: Multigenerational epigenetic adaptation of the hepatic wound-healing response
Author: Zeybel, M.
Hardy, T.
Wong, Y.
Mathers, J.
Fox, C.
Gackowska, A.
Oakley, F.
Burt, A.
Wilson, C.
Anstee, Q.
Barter, M.
Masson, S.
Elsharkawy, A.
Mann, D.
Mann, J.
Citation: Nature Medicine, 2012; 18(9):1369-1377
Publisher: Nature Publishing Group
Issue Date: 2012
ISSN: 1078-8956
1546-170X
Statement of
Responsibility: 
Müjdat Zeybel, Timothy Hardy, Yi K Wong, John C Mathers, 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
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.
Keywords: Spermatozoa
Mesenchymal Stem Cells
Animals
Humans
Rats
Liver Diseases
Actins
Histones
PPAR gamma
Blotting, Western
Immunohistochemistry
Adaptation, Biological
Wound Healing
DNA Methylation
Acetylation
Male
Transforming Growth Factor beta1
Myofibroblasts
Real-Time Polymerase Chain Reaction
Rights: © 2012 Nature America Inc. All Rights Reserved.
DOI: 10.1038/nm.2893
Appears in Collections:Aurora harvest
Medicine publications

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