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

Assante, G.; Chandrasekaran, S.; Ng, S.; Tourna, A.; Chung, C. H.; Isse, K. A.; Filippi, C.; Dhawan, A.; Liu, M.; Rozen, S. G.; Hoare, M.; Campbell, P.; Ballard, J. W. O.; Turner, N.; Morris, M. J.; Chokshi, S.; Youngson, N. A.

doi:10.1101/2021.07.22.453333

bioRxiv · 10.1101/2021.07.22.453333

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

Assante, G.·Chandrasekaran, S.·Ng, S.·Tourna, A.·Chung, C. H.·Isse, K. A.·Filippi, C.·Dhawan, A.·Liu, M.·Rozen, S. G.·Hoare, M.·Campbell, P.·Ballard, J. W. O.·Turner, N.·Morris, M. J.·Chokshi, S.·Youngson, N. A.

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Abstract

The rate of nonalcoholic 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. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker {gamma}H2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and {gamma}H2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

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Assante, G., Chandrasekaran, S., Ng, S., Tourna, A., Chung, C. H., Isse, K. A., Filippi, C., Dhawan, A., Liu, M., Rozen, S. G., Hoare, M., Campbell, P., Ballard, J. W. O., Turner, N., Morris, M. J., Chokshi, S., Youngson, N. A.. 2021-07-23. Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease. https://doi.org/10.1101/2021.07.22.453333

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