The role of chromatin remodeling factors in non-alcoholic fatty liver disease and carcinogenesis

• Applicant: Dr. Indrabahadur Singh, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421743046

Already, almost a quarter of the world's population suffers from non-alcoholic fatty liver (NAFLD) and this problem is steadily increasing. Non-alcoholic steatohepatitis (NASH), the chronic progressive manifestation of NAFLD, is the second most important cause of hepatocellular carcinoma (HCC). NAFLD thus represents a major socio-economic burden on the health care system and is of increasing importance. There are currently no drugs nor therapies that can treat NASH or stop the progression of the disease to HCC. At the same time, treatment options for HCC are limited and many patients show resistance to sorafenib, the only drug currently approved for first-line therapy. Although there have been major advances uncovering the genetic basis for NAFLD and HCC, the epigenetic mechanisms driving HCC remains largely elusive. Nevertheless, recent studies suggest epigenetic manipulation could be a promising approach to prevent the progression of NAFLD and HCC. Histone deacetylase inhibitors (e.g. Verinostat, PXD-101, Resminostat) are under clinical trials for HCC therapy. Epigenetic mechanisms underlying NAFLD progression remain elusive. Therefore, we will systematically investigate epigenetic changes facilitating NASH, transition to HCC and intratumoral heterogeneity in recently established our diet-induced NASH/HCC mouse models that recapitulate pathophysiological aspects of human NASH/HCC (Wolf MJ et al, Cancer Cell 2014) and in human samples employing functional genomic approaches (e.g. ChIP-seq, scNMT-seq). Identified putative targets will be exploited for developing potential therapeutics and diagnostics for this deadly disease. I have a strong expertise in epigenetics and functional genomics. I have identified a new epigenetic machinery (Singh I et al, Nat Genet 2018; Singh I et al, Cell Res 2015; Singh I et al, BMC Biol 2014) that links the mechanical process of chromatin organization and packaging with deregulation of oncogenes and tumor suppressors. This newly identified epigenetic machinery is also disrupted in pulmonary fibrosis. Using a small molecule inhibitor targeting a repressor of this complex, we were able to stabilize this epigenetic machinery and thereby block pulmonary fibrosis in vivo (Rubio K et al, Nat Commun 2018 under review). Fibrosis is an intermediate step of NAFLD progression to HCC. Therefore, I hypothesize that deregulation of this newly identified epigenetic machinery drives NAFLD progression to HCC. We will elucidate whether modulating this novel epigenetic machinery in NASH patients suffices to attenuate progression of NASH to HCC. In addition, our findings will shed further light on the underlying epigenetic mechanisms driving NASH-HCC pathogenesis and potentially uncover novel therapeutic targets for this lethal disease.

• DFG Programme: Independent Junior Research Groups