Multigenerational epigenetic adaptation of the hepatic wound-healing response

被引：204

作者：

Zeybel, Muejdat ^{[1
]}

Hardy, Timothy ^{[1
]}

Wong, Yi K. ^{[2
]}

Mathers, John C. ^{[2
]}

Fox, Christopher R. ^{[1
]}

Gackowska, Agata ^{[1
]}

Oakley, Fiona ^{[1
]}

Burt, Alastair D. ^{[1
]}

Wilson, Caroline L. ^{[1
]}

Anstee, Quentin M. ^{[1
]}

Barter, Matt J. ^{[1
]}

Masson, Steven ^{[1
]}

Elsharkawy, Ahmed M. ^{[1
]}

Mann, Derek A. ^{[1
]}

Mann, Jelena ^{[1
]}

机构：

[1] Newcastle Univ, Fac Med Sci, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[2] Newcastle Univ, Inst Ageing & Hlth, Ctr Brain Ageing & Vital, Human Nutr Res Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

来源：

NATURE MEDICINE | 2012年 / 18卷 / 09期

基金：

美国国家卫生研究院; 英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会; 英国医学研究理事会; 英国经济与社会研究理事会; 英国惠康基金;

关键词：

STELLATE CELL ACTIVATION; DNA METHYLATION; CHROMATIN-STRUCTURE; GENE-EXPRESSION; NONCODING RNAS; LIVER FIBROSIS; FATTY LIVER; TGF-BETA; HISTONE; PROGRESSION;

D O I：

10.1038/nm.2893

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1369 / +

页数：11

共 54 条

[1] Active Demethylation of Paternal Genome in Mammalian Zygotes [J].