"In this proposal we will study the role of histone methytransferases Set9, PR-SET7, Smyd2, Smyd3 and the demethylase LSD1 in hepatocarcinogenesis and in the regulation of hepatic metabolic pathways.The hypothesis raised here suggests that the function of histone modifying enzymes is realized through 4 overlapping regulatory layers: i. via modifications of chromatin, ii. via modifications of recently identified transcription factor substrates, iii. via influencing the hepatic transcription factor crossregulatory circuitry, and iv. via modification of each other.To dissect the role of these regulatory layers and determine their contribution in the control of hepatic metabolic pathways, and in the development of hepatocellular carcinoma, our activities will involve: i. Generation of relevant KO and transgenic mouse models, ii. Functional characterization of novel non-histone and histone substrates, iii. Analysis of novel cross-regulatory protein modifications affecting the activity of the enzymes and iv. the identification of their genomic targets and associated chromatin modifications using global approaches.The work is expected to provide important insights into a previously unanticipated network of protein methylation-directed regulatory modules, potentially operating in multiple biological pathways such as liver development, metabolism, apoptosis and carcinogenesis. The functioning of such network would be of high biological importance, with far-reaching implications in drug development, rivaling those of phosphorylation or acetylation regulated processes."