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

描述(申请人提供)：生物钟控制着一系列显著的生理和代谢功能。这种调节是通过由复杂的分子机制操作的转录-翻译循环网络来实现的。我们一直对解剖生物钟的分子齿轮感兴趣，这是一个控制着基因组的很大一部分(10%-20%的基因)的调控系统。我们最近的研究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。复杂的基因表达程序以昼夜节律为特征，代表了染色质转变中动态变化的范例。越来越多的证据表明，组蛋白脱乙酰酶SIRT1参与了昼夜节律的调节，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联系起来。然而，我们实验室最近的结果表明，SIRT1并不是整个故事的全部：其他sirtuins在细胞核中运行，其中之一SIRT6与染色质密切相关，已被证明在细胞新陈代谢中发挥关键作用。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的一种新功能，这是一种新的昼夜调控途径，也是SIRT6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在昼夜节律中如何以及何时运作。为了做到这一点，我们将采用一些分子、遗传和生理方法。这项提议的最终目标是深入了解染色质重塑和代谢途径与生物钟相连的分子机制。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影响 生理学和疾病。 与公共健康相关：生物钟控制着大量的生理和代谢功能。最近的研究结果表明，SIRT1是昼夜节律表观基因组的关键调控因子。在这里，我们揭示了另一个核sirtuin，SIRT6，也是时钟功能的关键， 为阐明sirtuins之间的第一个功能相互作用奠定了基础。

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. PUBLIC HEALTH RELEVANCE: The circadian clock controls a large array of physiological and metabolic functions. Recent results have shown that SIRT1 is a key regulator of the circadian epigenome. Here we reveal that another nuclear sirtuin, SIRT6, is also critical for clock function, and establish the basis to elucidate the first functional interplay between sirtuins.