Not Only SIRT1: A Role for Nuclear SIRT6 in Circadian Control

描述（由申请人提供）：生物钟控制着一系列显著的生理和代谢功能。这种调节是通过复杂的分子机制操作的转录-翻译循环网络实现的。我们一直对剖析生物钟的分子齿轮很感兴趣，生物钟是一个控制着很大一部分基因组（10-20%的基因）的调节系统。我们最近的研究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。基因表达的复杂程序表征了昼夜节律，它代表了染色质过渡动态变化的范式。越来越多的证据表明，组蛋白去乙酰化酶SIRT1参与昼夜节律调节，这是一个关键的发现，因为该酶利用NAD+作为辅酶，从而将能量代谢与昼夜节律调节联系起来。然而，我们实验室最近的结果表明，SIRT1不能是全部：其他sirtuins在细胞核中起作用，其中一个SIRT6与染色质密切相关，并已被证明在细胞代谢中起关键作用。我们的初步数据清楚地表明SIRT6在昼夜节律调节中起着关键作用，这表明SIRT1和SIRT6可能在控制昼夜节律基因表达和组蛋白乙酰化的功能上相互作用。这些结果揭示了SIRT6的一个新功能，一个新的昼夜节律控制途径和sirtuins之间相互作用的第一个例子。因此，该提案的目的是充分阐明SIRT6如何以及何时在昼夜周期中起作用。为此，我们将采用一些分子、遗传和生理方法。本研究的最终目标是深入了解染色质重塑和代谢途径与生物钟耦合的分子机制。由于表观遗传控制是细胞可塑性的分子基础，这些发现对人类具有深远的意义

DESCRIPTION (provided by applicant): The circadian clock controls a remarkable array of physiological and metabolic functions. This regulation is achieved through a network of transcriptional-translational loops operated by a complex molecular machinery. We have been interested in dissecting the molecular gears of the circadian clock, a regulatory system that governs a significant fraction of the genome (10-20% of the genes). Our recent research has revealed unexpected links between circadian regulators, chromatin remodeling and cellular metabolism. Complex programs of gene expression characterize circadian rhythms that represent a paradigm for dynamic changes in chromatin transitions. Accumulating evidence has implicated the histone deacetylase SIRT1 in circadian regulation, a key discovery since this enzyme utilizes NAD+ as coenzyme, thereby linking energy metabolism to circadian regulation. Recent results in our laboratory however indicate that SIRT1 can't be the whole story: other sirtuins operate in the nucleus and one of them, SIRT6, is tightly associated to chromatin and has been shown to play a critical role in cellular metabolism. Our preliminary data clearly show that SIRT6 plays a critical role in circadian regulation, suggesting the fascinating possibility tht SIRT1 and SIRT6 may functionally interplay in the control a circadian gene expression and histone acetylation. These results reveal a novel function of SIRT6, a novel pathway of circadian control and the first example of interplay between sirtuins. The aims of the proposal are thereby to fully elucidate how and when SIRT6 operates in the circadian cycle. To do so, we will employ a number of molecular, genetic and physiological approaches. The final goal of this proposal is to obtain an intimate understanding of the molecular mechanisms through which chromatin remodeling and metabolic pathways are coupled to the circadian clock. As epigenetic control is the molecular basis of cellular plasticity, these findings have far-reaching implications for human physiology and disease.