SIRT1 and MLL1 Interplay in circadian clock function

描述(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，并适当地在时间上改变行为和生理功能。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/食物摄入量和激素水平)。生物钟通过与每日的明暗周期同步进行自我调整。这些节律的紊乱会严重影响人类健康，导致失眠、抑郁、冠状动脉疾病、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、染色质重塑和细胞代谢之间意想不到的联系。依赖NAD+的SIRT1酶的HDAC活性是以昼夜节律的方式调节的，SIRT1将细胞代谢物产生的信号传递到昼夜节律时钟。我们的目标是通过了解两个染色质重构体SIRT1和组蛋白甲基转移酶MLL1之间相互作用的生化方面，获得控制昼夜节律基因表达模式的染色质转变调控的新见解。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，导致了对昼夜节律基因表达的全局控制。我们将揭开这两个关键的表观遗传调控因子协调其功能的尚未探索的分子机制。这项研究具有创新性，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.