title: Multigenerational epigenetic adaptation of the hepatic wound-healing response.
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.
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Müjdat
authors.initials: M
authors.lastname: Zeybel
authors.forename: Timothy
authors.initials: T
authors.lastname: Hardy
authors.forename: Yi K
authors.initials: YK
authors.lastname: Wong
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Fox
authors.forename: Agata
authors.initials: A
authors.lastname: Gackowska
authors.forename: Fiona
authors.initials: F
authors.lastname: Oakley
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Burt
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Wilson
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Barter
authors.forename: Steven
authors.initials: S
authors.lastname: Masson
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Elsharkawy
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
mesh_terms: D000107:Acetylation; D000199:Actins; D000220:Adaptation, Biological / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D019175:DNA Methylation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D058628:Myofibroblasts / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013094:Spermatozoa / Q000737:chemistry*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D006657:Histones; D047495:PPAR gamma; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat