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dc.contributor.authorAssante, Gabriella
dc.contributor.authorChandrasekaran, Sriram
dc.contributor.authorNg, Stanley
dc.contributor.authorTourna, Aikaterini
dc.contributor.authorChung, Carolina H
dc.contributor.authorIsse, Kowsar A
dc.contributor.authorBanks, Jasmine L
dc.contributor.authorSoffientini, Ugo
dc.contributor.authorFilippi, Celine
dc.contributor.authorDhawan, Anil
dc.contributor.authorLiu, Mo
dc.contributor.authorRozen, Steven G
dc.contributor.authorHoare, Matthew
dc.contributor.authorCampbell, Peter
dc.contributor.authorBallard, J William O
dc.contributor.authorTurner, Nigel
dc.contributor.authorMorris, Margaret J
dc.contributor.authorChokshi, Shilpa
dc.contributor.authorYoungson, Neil A
dc.date.accessioned2022-06-29T19:44:59Z
dc.date.available2022-06-29T19:44:59Z
dc.date.issued2022-06-23
dc.date.submitted2021-08-10
dc.identifier.issn1756-994X
dc.identifier.others13073-022-01071-5
dc.identifier.other1071
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338494
dc.descriptionFunder: foundation for liver research; doi: http://dx.doi.org/10.13039/501100000404
dc.descriptionFunder: Camille and Henry Dreyfus Foundation; doi: http://dx.doi.org/10.13039/100001082
dc.description.abstractBACKGROUND: 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.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectResearch
dc.subjectSteatosis
dc.subjectHistone acetylation
dc.subjectHepatocellular carcinoma
dc.subjectNAFLD
dc.subjectARLD
dc.subjectTelomerase
dc.titleAcetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease.
dc.typeArticle
dc.date.updated2022-06-29T19:44:58Z
prism.issueIdentifier1
prism.publicationNameGenome Med
prism.volume14
dc.identifier.doi10.17863/CAM.85907
dcterms.dateAccepted2022-06-16
rioxxterms.versionofrecord10.1186/s13073-022-01071-5
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHoare, Matthew [0000-0001-5990-9604]
dc.identifier.eissn1756-994X
pubs.funder-project-idaustralian research council (DP190102555)
pubs.funder-project-idsingapore ministry of health via the duke-nus signature research programmes (MOH-000032/MOH-CIRG18may-0004)
pubs.funder-project-idNational Institute of Health (US) (R35 GM13779501)
pubs.funder-project-idCRUK-OHSU Project Award ((C52489/A29681))
pubs.funder-project-idCRUK Accelerator award to the HUNTER consortium ((C18873/A26813).)
cam.issuedOnline2022-06-23


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