Multigenerational epigenetic adaptation of the hepatic wound-healing response

Abstract

We asked if ancestral liver damage leads to heritable reprogramming of hepatic wound-healing. We discovered that male rats with a history of liver damage transmit epigenetic suppressive adaptation of the fibrogenic component of wound-healing through male F1 and F2 generations. Underlying this adaptation was reduced generation of liver myofibroblasts, increased hepatic expression of antifibrogenic PPAR-γ and decreased expression of profibrogenic TGF-β1. Remodelling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for H2A.Z and H3K27me3 at PPAR-γ chromatin. These sperm chromatin modifications were transmittable by adaptive serum transfer from fibrotic rats and were induced in stem cells exposed to myofibroblast-conditioned media. A myofibroblast secreted soluble factor therefore stimulates heritable epigenetic signatures to sperm so as to adapt fibrogenesis in offspring. Humans with mild liver fibrosis display PPAR-γ promoter hypomethylation compared with severe fibrotics, thus lending support for epigenetic regulation of fibrosis.