Alcoholic cirrhosis is the most prevalent and devastating medical consequence of alcohol abuse with no efficacious treatment except for liver transplantation. Myofibroblastic transdifferentiation of hepatic stellate cells (HSCs) commonly called HSC activation, constitutes a major mechanistic event in alcoholic liver fibrosis. We hypothesize epigenetic regulation dictates this cell fate regulation and serves as a most plausible therapeutic target. In support of this hypothesis, our research conducted to date revealed the methyl-CpG binding protein MeCP2 orchestrates epigenetic HSC activation via: 1) repression of the HSC quiescence gene Ppar- via recruitment of HP1 co-repressor and EZH2-mediated H3K27 di- or tri-methylation; 2) up regulation of ASH1 histone methyltransferase which in turn induces fibrogenic genes such as Col1a1, aSma, Timp1, Tgf-1 via H3K4 methylation. [We also demonstrated conspicuous upregulation of another H3K4 methyltrasferase, MLL1 and co-enrichment of MLL1 and H3K4me3 in a uniquely segregated set of genes with potential activation roles by combinatorial ChIP-seq and RNA-seq analyses.] Via international collaboration of three leading laboratories with complementary expertise, we propose to extend these novel findings to further define the causal roles of MeCP2, ASH1, and MLL1 in HSC activation and alcoholic liver fibrosis by pursuing the following specific aims: [1) to determine whether inducible and activated HSC- targeted MeCP2 deficiency prevents the progression of alcoholic liver fibrosis by using mice harboring MeCP2f/y and Col1a1-CreERT; 2) to discover how MeCP2 and the H3K4 HAT ASH1 and MLL1 render epigenetic activation of HSCs in alcoholic liver fibrogenesis; 3) to determine whether there is epigenetic control of HSC phenotype reversion and whether epigenetic memory is causally associated with increased re-activation propensity of iHSCs by using Col1a2-CreERT:Rosa26flox-stop-flox-YFP mice and FACS-based isolation of HSCs at the peak of alcoholic liver fibrosis and after resolution from fibrosis. ]
The propose study will generate most leading-edge information concerning how epigenetic reprogramming causes activation and re-activation of hepatic stellate cells and alcoholic liver fibrosis, knowledge which is most essential in developing new mechanism-based therapeutic modalities for the disease.
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