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Epigenetics and Circadian Clock: deciphering the physiological and molecular path

表观遗传学和昼夜节律时钟：破译生理和分子路径

基本信息

批准号：
7769499
负责人：
Paolo Sassone-Corsi
金额：
$ 15.53万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7769499
关键词：
Acetylation Acyl Coenzyme A Antibodies Behavioral Binding Biochemical Cells Chromatin Circadian Rhythms Clock protein Complex Coronary heart disease Cultured Cells Deacetylase Energy Metabolism Enzymes Epigenetic Process Event Fatty Acids Gene Targeting Generations Genes Genetic Transcription Glucose Health Hepatocyte Histone Deacetylase Histones Hormonal Human In Vitro Laboratories Life Link Liver Lysine Malignant Neoplasms Mass Spectrum Analysis Mediating Mental Depression Metabolic Metabolism Methods Molecular Mus Neurodegenerative Disorders Nuclear Receptors Organism Pathway interactions Physiological Physiology Procedures Proteins Regulation Series Sleep Disorders Sleep Wake Cycle System Techniques Therapeutic Time Transcript Transcriptional Regulation Xenobiotic Metabolism base chromatin remodeling circadian pacemaker environmental change fatty acid metabolism genome-wide glucose metabolism histone acetyltransferase in vivo insight liver metabolism multicatalytic endopeptidase complex novel public health relevance research study response thioester tool development

项目摘要

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.

描述(申请人提供)：在大多数生物体内，昼夜节律支配着大量的生理、生化和行为反应。生物钟是一种内在的时间跟踪系统，能够适应环境的变化。昼夜节律紊乱对人类健康有深远的影响，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(细胞(2006)125：497-508；自然(2007)450,1086-90；细胞(2008)在出版中)建立了时钟，一个昼夜节律的主要调节者，直接乙酰化组蛋白及其伴侣BMAL1。Clock固有的HAT酶活性表明，控制染色质重塑是调控昼夜节律时钟机制的关键步骤。在寻找时钟的非组蛋白底物的过程中，我们探索了核受体以昼夜节律的方式乙酰化的可能性。生物钟中存在一个假定的核受体相互作用结构域(NRID)，昼夜生理学与某些不同的核受体对新陈代谢的调节之间存在密切联系，这支持了这种可能性。我们的初步研究已经确定HNF-4是一个特权时钟靶标。这一提议的核心是破译这一事件的分子、功能和生理意义。HNF-4是一种核受体，控制肝脏代谢和肝细胞分化。它的活性可能受脂肪酸酰基-辅酶A硫代酯结合的调节，并与葡萄糖代谢的控制有关，并间接与异源代谢有关。因此，我们已经确定了一种具有多种分子和生理意义的分子联系，并为一些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学和新陈代谢提供新的和重要的见解。与公共健康相关：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控制肝脏新陈代谢的关键因素--核受体HNF4--的密切机制。这些研究将为表观遗传过程如何控制昼夜生理学和新陈代谢提供新的和重要的见解。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The histone methyltransferase MLL1 permits the oscillation of circadian gene expression.

组蛋白甲基转移酶MLL1允许昼夜节律表达的振荡。

DOI：
10.1038/nsmb.1961
发表时间：
2010-12
期刊：
Nature structural & molecular biology
影响因子：
16.8
作者：
Katada S;Sassone-Corsi P
通讯作者：
Sassone-Corsi P

PER2 controls lipid metabolism by direct regulation of PPARγ.

DOI：
10.1016/j.cmet.2010.10.005
发表时间：
2010-11-03
期刊：
Cell metabolism
影响因子：
29
作者：
Grimaldi B;Bellet MM;Katada S;Astarita G;Hirayama J;Amin RH;Granneman JG;Piomelli D;Leff T;Sassone-Corsi P
通讯作者：
Sassone-Corsi P

Regulation of spermatogenesis by small non-coding RNAs: role of the germ granule.