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

Gabriella Assante; Sriram Chandrasekaran; Stanley Ng; Aikaterini Tourna; Carolina H Chung; Kowsar A Isse; Jasmine L Banks; Ugo Soffientini; Celine Filippi; Anil Dhawan; Mo Liu; Steven G Rozen; Matthew Hoare; Peter Campbell; J William O Ballard; Nigel Turner; Margaret J Morris; Shilpa Chokshi; Neil A Youngson

doi:10.1186/s13073-022-01071-5

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

Genome Med. 2022 Jun 23;14(1):67. doi: 10.1186/s13073-022-01071-5.

Authors

Gabriella Assante^{1

2}, Sriram Chandrasekaran^{3

4

5

6}, Stanley Ng⁷, Aikaterini Tourna^{1

2}, Carolina H Chung⁵, Kowsar A Isse^{1

2}, Jasmine L Banks^{8

9}, Ugo Soffientini^{1

2}, Celine Filippi¹⁰, Anil Dhawan¹⁰, Mo Liu¹¹, Steven G Rozen¹¹, Matthew Hoare^{12

13}, Peter Campbell⁷, J William O Ballard¹⁴, Nigel Turner^{8

9}, Margaret J Morris⁸, Shilpa Chokshi^{1

2}, Neil A Youngson^{15

16

17}

Affiliations

¹ Institute of Hepatology, Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.
² King's College London, Faculty of Life Sciences and Medicine, London, UK.
³ Program in Chemical Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴ Center for Bioinformatics and Computational Medicine, Ann Arbor, MI, 48109, USA.
⁵ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
⁷ Wellcome Trust Sanger Institute, Cambridge, UK.
⁸ UNSW Sydney, Sydney, Australia.
⁹ Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
¹⁰ Institute of Liver Studies, King's College Hospital, London, UK.
¹¹ Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
¹² CRUK Cambridge Institute, Cambridge, UK.
¹³ Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
¹⁴ Department of Ecology, Environment and Evolution, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia.
¹⁵ Institute of Hepatology, Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK. n.youngson@researchinliver.org.uk.
¹⁶ King's College London, Faculty of Life Sciences and Medicine, London, UK. n.youngson@researchinliver.org.uk.
¹⁷ UNSW Sydney, Sydney, Australia. n.youngson@researchinliver.org.uk.

Abstract

Background: The 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.

Methods: Global 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.

Results: Genome-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.

Conclusions: Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.

Keywords: ARLD; Hepatocellular carcinoma; Histone acetylation; NAFLD; Steatosis; Telomerase.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Acetyl Coenzyme A / metabolism
Animals
Carcinogenesis / pathology
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Diet, High-Fat / adverse effects
Epigenome
Fructose / adverse effects
Fructose / metabolism
Histones / metabolism
Humans
Liver / metabolism
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / complications
Non-alcoholic Fatty Liver Disease* / genetics

Substances

Histones
Fructose
Acetyl Coenzyme A

Grants and funding

R35 GM13779501/National Institute of Health (US)