Chromatin Remodeling and Circadian Clock Control

描述(申请人提供)：大多数生物体的许多基本生理功能都是由生物钟控制的。这是大多数生物体固有的时间跟踪系统，使其能够适应环境变化。昼夜节律紊乱对人类健康有深远的影响，并与抑郁、失眠、时差、冠心病和各种神经退行性疾病有关。因此，控制生物钟的分子机制对于理解生理学和新陈代谢的联系是非常有吸引力的，为开发治疗策略提供了潜在的工具。值得注意的是，10%-15%的哺乳动物转录本的表达水平经历了昼夜波动。因此，全基因组机制必须运作，以确保这种全球转录调控。我们最近的研究(Cell 2006 125：497-508)已经证实，时钟是昼夜节律的主控制器，直接修改染色质。Clock具有内源性的组蛋白乙酰转移酶(HAT)活性，表明染色质重塑的控制是调控生物钟机制的关键步骤。这一发现具有多种分子和生理意义，并为一些重要的体外和体内研究铺平了道路，这些研究是这一提议的核心。我们将使用一系列分子、遗传和生化方法来深入了解染色质重塑机制，这些机制可能控制生物钟的生理机制。另一个目标是解开时钟介导的信号如何与时钟的酶功能‘对话’，从而在生理学和染色质重塑之间建立直接联系。最终的目标是通过鉴定其酶活性的天然底物来破译时钟介导的乙酰化的程度。我们预测，这些研究将为染色质重塑如何控制昼夜生理学和新陈代谢提供新的和重要的见解。生物钟控制着我们各种各样的节律生理，包括睡眠-觉醒周期、新陈代谢和荷尔蒙水平。这项提议旨在破译生物钟运行的亲密机制。具体地说，我们将揭开染色质在这些过程中的功能，染色质是DNA的蛋白质支架。

DESCRIPTION (provided by applicant): A remarkable variety of fundamental physiological functions in most organisms is controlled by the circadian clock. This is a time-tracking system intrinsic to most organisms that enables the adaptation to environmental changes. Disruption of circadian rhythms has profound influence to human health and has been linked to depression, insomnia, jet lag, coronary heart disease and a variety of neurodegenerative diseases. 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) have established that CLOCK, a master controller of circadian rhythms, directly modifies chromatin. CLOCK possesses intrinsic enzymatic histone acetyltransferase (HAT) activity, demonstrating that control of chromatin remodeling constitutes a key regulatory step governing the circadian clock machinery. This finding has multiple molecular and physiological implications and paves the way to a number of important in vitro and in vivo studies that are central to this proposal. We will use a range of molecular, genetic and biochemical approaches to gain insights into chromatin remodeling mechanisms that are likely to govern the physiological mechanism of the circadian clock. Another goal is to unravel how clock-mediated signaling may 'talk' to the enzymatic function of CLOCK, and thereby establish a direct link between physiology and chromatin remodeling. A final goal is to decipher the extent of CLOCK-mediated acetylation, by identifying the natural substrates of its enzymatic activity. We predict that these studies will provide novel and important insights into how circadian physiology and metabolism are controlled by chromatin remodeling. 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 operates. Specifically, we will unravel the function that chromatin, the proteinaceous scaffold of DNA, has in these processes.