SIRT1 and MLL1 Interplay in circadian clock function

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DESCRIPTION (provided by applicant): The correct functioning of the endogenous circadian clock enables organisms to anticipate daily environmental changes and temporally modify behavioral and physiological functions appropriately. All organisms maintain a large number of physiological variables (sleep-wake cycle, locomotor activity, temperature regulation, water/food intake and levels of hormones) under control of the circadian clock. The biological clock readjusts itself by synchronizing to the daily light-dark cycle. Disruption of these rhythms has drastic effects on human health, leading to insomnia, depression, coronary diseases, various neurodegenerative or metabolic disorders and cancer. Recent advances have revealed unexpected links between circadian regulators, chromatin remodeling and cellular metabolism. The HDAC activity of the NAD+dependent SIRT1 enzyme is regulated in a circadian manner and SIRT1 transduces signals originated by cellular metabolites to the circadian clock. We aim to gain new insights into the regulation of chromatin transitions that govern the expression pattern of circadian genes, by understanding the biochemical aspects of the interaction between two chromatin remodelers, SIRT1 and MLL1, a histone methyltransferase. Our preliminary results convincingly indicate that MLL1 is acetylated and it is directly regulated by SIRT1, leading to a global control of circadian gene expression. We will unravel yet unexplored molecular mechanisms in which these two critical epigenetic regulators coordinate their function. This line of research is innovative as it links specific metabolic pathways to the epigenetic control of chromatin remodeling. PUBLIC HEALTH RELEVANCE: The role of chromatin remodeling in circadian gene expression is emerging. This proposal is centered on the molecular interplay between SIRT1 and MLL1, two regulators implicated in the processes of aging, metabolism and cell proliferation. The research proposed may lead to innovative strategies for pharmaceutical intervention.