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. ]

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA018663-07
Application #
9125700
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Gao, Peter
Project Start
2010-09-01
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Mann, Jelena; Reeves, Helen L; Feldstein, Ariel E (2018) Liquid biopsy for liver diseases. Gut 67:2204-2212
Wilson, Caroline L; Mann, Derek A; Borthwick, Lee A (2017) Epigenetic reprogramming in liver fibrosis and cancer. Adv Drug Deliv Rev 121:124-132
Yang, Zemin; Liu, Yu; Qin, Lan et al. (2017) Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 187:781-797
Madakashira, Bhavani; Corbett, Laura; Zhang, Chi et al. (2017) Variant Histone H2afv reprograms DNA methylation during early zebrafish development. Epigenetics 12:811-824
Lai, Keane K Y; Kweon, Soo-Mi; Chi, Feng et al. (2017) Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology 152:1477-1491
Zeybel, M├╝jdat; Luli, Saimir; Sabater, Laura et al. (2017) A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A. Mol Ther 25:218-231
Eguchi, Akiko; Lazaro, Raul G; Wang, Jiaohong et al. (2017) Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 65:475-490
McDaniel, Kelly; Huang, Li; Sato, Keisaku et al. (2017) The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury. J Biol Chem 292:11336-11347
Hardy, Timothy; Zeybel, Mujdat; Day, Christopher P et al. (2017) Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 66:1321-1328
Mandrekar, Pranoti; Bataller, Ramon; Tsukamoto, Hidekazu et al. (2016) Alcoholic hepatitis: Translational approaches to develop targeted therapies. Hepatology 64:1343-55

Showing the most recent 10 out of 29 publications