Epigenetics and Circadian Clock: deciphering the physiological and molecular path

描述（由申请人提供）：在大多数生物体中，昼夜节律主导着大量的生理、生化和行为反应。生物钟是一种内在的时间跟踪系统，能够适应环境变化。昼夜节律紊乱对人类健康有深远影响，并与抑郁症、睡眠障碍、冠心病、代谢紊乱、神经退行性疾病和癌症有关。因此，控制生物钟的分子机制对于理解生理和代谢的联系是非常有吸引力的，代表了开发治疗策略的潜在工具。值得注意的是，10-15%的哺乳动物转录本在其表达水平上经历昼夜波动。因此，全基因组机制必须运作，以确保这种全球转录调节。我们最近的研究(Cell (2006) 125: 497-508；自然（2007）450,1086-90；Cell（2008年出版）已经确定，昼夜节律的主要调节因子CLOCK可以直接使组蛋白及其伙伴BMAL1乙酰化。生物钟内在的HAT酶活性表明，染色质重塑的控制构成了生物钟机制的关键调控步骤。在寻找CLOCK的非组蛋白底物时，我们已经探索了核受体可能以昼夜节律方式乙酰化的可能性。这种可能性是由CLOCK中假定的NRID（核受体相互作用域）的存在以及一些不同的核受体对代谢的调节与昼夜生理之间存在的密切联系所支持的。我们的初步研究已经确定HNF-4是一个特殊的CLOCK靶点。本提案的核心是解读这一事件的分子、功能和生理意义。HNF-4是一种控制肝脏代谢和肝细胞分化的核受体。它的活性可以通过脂肪酸酰基辅酶a硫酯的结合来调节，并与葡萄糖代谢的控制有关，间接地与外源代谢有关。因此，我们已经确定了一个具有多种分子和生理意义的分子联系，并为许多重要的体外和体内研究铺平了道路。我们预测这些研究将为表观遗传过程如何控制昼夜生理和代谢提供新颖而重要的见解。公共卫生相关性：生物钟控制着我们大量的节律生理，包括睡眠-觉醒周期、新陈代谢和激素水平。这一建议旨在破译昼夜节律钟控制肝脏代谢关键参与者核受体HNF4的内在机制。这些研究将为表观遗传过程如何控制昼夜生理和代谢提供新颖而重要的见解。

DESCRIPTION (provided by applicant): Circadian rhythms dominate a large array of physiological, biochemical and behavioral responses in most living organisms. The circadian clock is an intrinsic time-tracking system that enables the adaptation to environmental changes. Disruption of circadian rhythms has profound influence to human health and has been linked to depression, sleep disorders, coronary heart disease, metabolic disturbances, neurodegenerative diseases and cancer. Thereby, the molecular mechanisms governing the circadian clock constitute a very attractive hold for the understanding of the links to physiology and metabolism, representing potential tools for the development of therapeutic strategies. Remarkably, 10-15% of all mammalian transcripts undergo circadian fluctuations in their expression levels. Thus, genome-wide mechanisms must operate in order to insure such global transcriptional regulation. Our recent studies (Cell (2006) 125: 497-508; Nature (2007) 450, 1086-90; Cell (2008) in press) have established that CLOCK, a master regulator of circadian rhythms, directly acetylates histones and its partner BMAL1. CLOCK intrinsic HAT enzymatic activity demonstrates that control of chromatin remodeling constitutes a key regulatory step governing the circadian clock machinery. In a search for non-histone substrates of CLOCK, we have explored the possibility that nuclear receptors could be acetylated in a circadian manner. This possibility is supported by the presence of a putative NRID (nuclear receptor interaction domain) in CLOCK and by the intimate links that exist between circadian physiology and regulation of metabolism by some distinct nuclear receptors. Our preliminary studies have identified HNF-4 as a privileged CLOCK target. This proposal is centered on deciphering the molecular, functional and physiological significance of this event. HNF-4 is a nuclear receptor which controls liver metabolism and hepatocyte differentiation. Its activity may be modulated by the binding of fatty acid acyl-CoA thioesters and has been linked to the control of glucose metabolism and, indirectly, to xenobiotic metabolism. Thus, we have identified a molecular link that has multiple molecular and physiological implications and paves the way to a number of important in vitro and in vivo studies. We predict that these studies will provide novel and important insights into how circadian physiology and metabolism are controlled by epigenetic processes. PUBLIC HEALTH RELEVANCE: The circadian clock governs a large variety of our rhythmic physiology, including sleep-wake cycles, metabolism and hormonal levels. This proposal is aimed at deciphering the intimate mechanisms by which the circadian clock controls a key player in liver metabolism, the nuclear receptor HNF4. These studies will provide novel and important insights into how circadian physiology and metabolism are controlled by epigenetic processes.