SIRT1 and MLL1 Interplay in circadian clock function

描述（由申请人提供）：内源性生物钟的正确功能使生物体能够预测日常环境变化，并适当地暂时调整行为和生理功能。所有生物体都在生物钟的控制下维持着大量的生理变量（睡眠-觉醒周期、运动活动、温度调节、水/食物摄入和激素水平）。生物钟通过与每天的明暗周期同步来重新调整自己。这些节律的破坏会对人类健康产生巨大影响，导致失眠、抑郁、冠心病、各种神经退行性或代谢紊乱以及癌症。最近的进展揭示了昼夜节律调节因子、染色质重塑和细胞代谢之间意想不到的联系。NAD+依赖性SIRT1酶的HDAC活性以昼夜节律方式调节，SIRT1将细胞代谢物产生的信号转导到昼夜节律钟。我们的目标是通过了解两种染色质重塑物SIRT1和MLL1（一种组蛋白甲基转移酶）之间相互作用的生化方面，对控制昼夜节律基因表达模式的染色质转变的调控获得新的见解。我们的初步结果令人信服地表明，MLL1是乙酰化的，它直接受到SIRT1的调控，导致昼夜节律基因表达的全局控制。我们将揭开尚未探索的分子机制，其中这两个关键的表观遗传调控协调其功能。这条研究路线是创新的，因为它将特定的代谢途径与染色质重塑的表观遗传控制联系起来。

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.