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Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: Dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis

Lookup NU author(s): Marina Barcena-Varela, Hannah Paish, Stuart Robinson, Jeremy French, Professor Fiona Oakley, Professor Jelena Mann

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Abstract

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Objective: Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We aimed to study the efficacy of CM272, a first-in-class dual and reversible G9a/DNMT1 inhibitor, in halting fibrogenesis. Design: G9a and DNMT1 were analysed in cirrhotic human livers, mouse models of liver fibrosis and cultured mouse HSC. G9a and DNMT1 expression was knocked down or inhibited with CM272 in human HSC (hHSC), and transcriptomic responses to transforming growth factor-β1 (TGFβ1) were examined. Glycolytic metabolism and mitochondrial function were analysed with Seahorse-XF technology. Gene expression regulation was analysed by chromatin immunoprecipitation and methylation-specific PCR. Antifibrogenic activity and safety of CM272 were studied in mouse chronic CCl4 administration and bile duct ligation (BDL), and in human precision-cut liver slices (PCLSs) in a new bioreactor technology. Results: G9a and DNMT1 were detected in stromal cells in areas of active fibrosis in human and mouse livers. G9a and DNMT1 expression was induced during mouse HSC activation, and TGFβ1 triggered their chromatin recruitment in hHSC. G9a/DNMT1 knockdown and CM272 inhibited TGFβ1 fibrogenic responses in hHSC. TGFβ1-mediated profibrogenic metabolic reprogramming was abrogated by CM272, which restored gluconeogenic gene expression and mitochondrial function through on-target epigenetic effects. CM272 inhibited fibrogenesis in mice and PCLSs without toxicity. Conclusions: Dual G9a/DNMT1 inhibition by compounds like CM272 may be a novel therapeutic strategy for treating liver fibrosis.


Publication metadata

Author(s): Barcena-Varela M, Paish H, Alvarez L, Uriarte I, Latasa MU, Santamaria E, Recalde M, Garate M, Claveria A, Colyn L, Arechederra M, Iraburu MJ, Milkiewicz M, Milkiewicz P, Sangro B, Robinson SM, French J, Pardo-Saganta A, Oyarzabal J, Prosper F, Rombouts K, Oakley F, Mann J, Berasain C, Avila MA, Fernandez-Barrena MG

Publication type: Article

Publication status: Published

Journal: Gut

Year: 2020

Pages: ePub ahead of print

Online publication date: 23/04/2020

Acceptance date: 29/03/2020

ISSN (print): 0017-5749

ISSN (electronic): 1468-3288

Publisher: BMJ Publishing Group

URL: https://doi.org/10.1136/gutjnl-2019-320205

DOI: 10.1136/gutjnl-2019-320205

PubMed id: 32327527


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