Chromatin Remodeling and Circadian Clock Control

描述（由申请人提供）：在大多数生物体中，各种各样的基本生理功能都是由生物钟控制的。这是大多数生物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着深远的影响，并与抑郁、失眠、时差反应、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）已经证实，生物钟是昼夜节律的主要控制者，可以直接改变染色质。CLOCK具有内在的酶组蛋白乙酰转移酶（HAT）活性，表明对染色质重塑的控制是控制生物钟机制的关键调控步骤。这一发现具有多种分子和生理意义，并为许多重要的体外和体内研究铺平了道路，这些研究是本提案的核心。我们将使用一系列分子、遗传和生化方法来深入了解可能控制生物钟生理机制的染色质重塑机制。另一个目标是揭示生物钟介导的信号如何与生物钟的酶促功能“对话”，从而在生理和染色质重塑之间建立直接联系。最后的目标是破译时钟介导的乙酰化程度，通过确定其酶活性的天然底物。我们预测这些研究将为染色质重塑如何控制昼夜生理和代谢提供新颖而重要的见解。生物钟控制着我们大量有节奏的生理活动，包括睡眠-觉醒周期、新陈代谢和荷尔蒙水平。这一建议旨在破译生物钟运作的内在机制。具体来说，我们将揭示染色质，DNA的蛋白质支架，在这些过程中的功能。

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.