Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis | Gut Skip to main content Subscribe Log In More Log in via Institution Log in via OpenAthens Log in via BSG Log in using your username and password For personal accounts OR managers of institutional accounts Username * Password * Forgot your log in details?Register a new account? Forgot your user name or password? Basket Search More Search for this keyword Advanced search Latest content Current issue Archive Authors About Hosted content Search for this keyword Advanced search Close More Main menu Latest content Current issue Archive Authors About Hosted content Subscribe Log in More Log in via Institution Log in via OpenAthens Log in via BSG Log in using your username and password For personal accounts OR managers of institutional accounts Username * Password * Forgot your log in details?Register a new account? Forgot your user name or password? BMJ Journals You are here Home Archive Volume 70, Issue 2 Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis Email alerts Article Text Article menu Article Text Article info Citation Tools Share Rapid Responses Article metrics Alerts PDF Hepatology Original research Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis Abstract 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. fibrogenesis glucose metabolism gene regulation http://dx.doi.org/10.1136/gutjnl-2019-320205 Statistics from Altmetric.com Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. 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