Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

Genome Medicine

Research

Matthew Hoare¹  Carolina H. Chung²  J. William O. Ballard³  Aikaterini Tourna⁴  Gabriella Assante⁴  Shilpa Chokshi⁴  Kowsar A. Isse⁴  Ugo Soffientini⁴  Neil A. Youngson⁵  Celine Filippi⁶  Anil Dhawan⁶  Sriram Chandrasekaran⁷  Steven G. Rozen⁸  Mo Liu⁸  Margaret J. Morris⁹  Jasmine L. Banks^1,10  Nigel Turner^1,10  Stanley Ng^1,11  Peter Campbell^1,11 

[1] CRUK Cambridge Institute, Cambridge, UK;Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK;Department of Biomedical Engineering, University of Michigan, 48109, Ann Arbor, MI, USA;Department of Ecology, Environment and Evolution, La Trobe University, 3086, Bundoora, Melbourne, VIC, Australia;Institute of Hepatology, Foundation for Liver Research, 111 Coldharbour Lane, SE5 9NT, London, UK;King’s College London, Faculty of Life Sciences and Medicine, London, UK;Institute of Hepatology, Foundation for Liver Research, 111 Coldharbour Lane, SE5 9NT, London, UK;King’s College London, Faculty of Life Sciences and Medicine, London, UK;UNSW Sydney, Sydney, Australia;Institute of Liver Studies, King’s College Hospital, London, UK;Program in Chemical Biology, University of Michigan, 48109, Ann Arbor, MI, USA;Center for Bioinformatics and Computational Medicine, 48109, Ann Arbor, MI, USA;Department of Biomedical Engineering, University of Michigan, 48109, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 48109, Ann Arbor, MI, USA;Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore;UNSW Sydney, Sydney, Australia;UNSW Sydney, Sydney, Australia;Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia;Wellcome Trust Sanger Institute, Cambridge, UK;

关键词: Steatosis;    Histone acetylation;    Hepatocellular carcinoma;    NAFLD;    ARLD;    Telomerase;   

DOI  :  10.1186/s13073-022-01071-5

 received in 2021-08-10, accepted in 2022-06-16,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis.MethodsGlobal epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD.ResultsGenome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism.ConclusionsAbnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2023

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