The Role of SIRT6 in Modulating Circadian Gene Expression

SIRT6 在调节昼夜节律基因表达中的作用

基本信息

批准号：
8126987
负责人：
Selma Masri
金额：
$ 5.13万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8126987
关键词：
Acetylation Address Affect Age Reporting Anterior Binding Biological Biology Chromatin Circadian Rhythms Deacetylase Deacetylation Depressed mood Disease Embryo Employee Strikes Event Family Family member Fibroblasts Gene Expression Gene Targeting Genes Genetic Transcription Glucose Goals Heart Hepatic Histone Deacetylase Histone H3 Histones Hour Hypoglycemia Hypothalamic structure In Vitro Knock-out Knockout Mice Laboratories Lead Link Lysine Mediating Mental Depression Metabolic Metabolic Syndrome X Molecular Molecular Profiling Mus Neurons Nuclear Nucleoplasm Pacemakers Pattern Periodicity Peripheral Phenotype Phosphorylation Physiologic Thermoregulation Physiological Processes Physiology Play Post-Translational Protein Processing Premature aging syndrome Production Proteins Regulation Regulator Genes Reporting Repression Role Serum Sirtuins Sleep Disorders Sleep Wake Cycle Specificity System Testing Time Transcriptional Regulation Work blood glucose regulation chromatin remodeling circadian pacemaker cryptochrome feeding gene repression histone acetyltransferase hormone regulation hypoxia inducible factor 1 in vivo novel promoter suprachiasmatic nucleus transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Circadian rhythms control the timing of numerous physiological processes over a 24-hour period, including sleep-wake cycles, thermoregulation, feeding, metabolic regulation and hormone production. At the heart of the molecular network that constitutes the circadian clock are the core transcription factors CLOCK and BMAL1 that heterodimerize, and in conjunction with the transcriptional machinery, direct rhythmic expression of clock-controlled genes (CCGs). A critical component of circadian gene expression is linked to CLOCK, a known histone acetyltransferase, which directs rhythmic acetylation of histone H3 lysine 9/14 as well as BMAL1. In terms of circadian transcription, little is known about the transcriptional machinery that works in concert with CLOCK and BMAL1 to direct circadian gene expression. The goal of this proposal is to elucidate the mechanisms of regulation of the mammalian sirtuins, class III histone deacetylases (HDACs), on circadian gene expression and biological rhythmicity in vivo. SIRT6 is a known chromatin-associated HDAC that directs deacetylation of histone H3 lysine 9 at relevant gene promoters, but SIRT6 has not been implicated in circadian biology. Of particular importance, SIRT1 is responsible for deacetylation and regulation of BMAL1, as well as deacetylation of H3 lysine 9/14 at circadian gene promoters. Surprisingly, SIRT1 is a nuclear sirtuin that is mostly localized in the nucleoplasm, therefore it in unclear whether the efficiency of SIRT1 is suited for histone targets or better directed towards non-histone proteins such as BMAL1. It is hypothesized that a functional interplay exists between SIRT6 and SIRT1 in modulating circadian gene expression, and that the subcellular localization of these sirtuins may dictate efficiency of deacetylase activity towards histone versus non-histone targets. It is hypothesized that the HDAC SIRT6 is associated with the core circadian transcription factors, CLOCK and BMAL1, and may be involved in modulating circadian gene expression by deacetylating H3K9 at circadian gene promoters, resulting in transcriptional repression and subsequent oscillation of CCG expression. To test this hypothesis, the use of wild-type and SIRT6 knockout mice as well as mouse embryo fibroblasts (MEFs) will be utilized to determine SIRT6-mediated effects on circadian gene expression in vitro and in vivo, and how these actions differ from SIRT1. PUBLIC HEALTH RELEVANCE: Circadian rhythms are inherent biological timekeeping mechanisms that regulate our daily physiology, and moreover, disruptions in the biological circadian clock can lead to numerous diseases including sleep disorders, depression, metabolic syndrome, cardiovascular disturbances and tumorigenesis. The goal of this proposal is to elucidate the mechanisms of regulation of circadian gene expression and ultimately the regulatory events in place that modulate circadian rhythms in vivo.

描述（由申请人提供）：昼夜节律在24小时内控制了许多生理过程的时间，包括睡眠效果循环，温度调节，进食，代谢调节和激素产生。构成昼夜节律时钟的分子网络的核心是核心转录因子时钟和BMAL1，它是异构二聚体的核心转录因子，并且与转录机械结合，时钟控制基因（CCGS）的直接节奏表达。昼夜节律基因表达的关键成分与时钟有关，这是一种已知的组蛋白乙酰转移酶，它指导组蛋白H3赖氨酸9/14和BMAL1的节奏乙酰化。就昼夜节律转录而言，对与时钟和BMAL1合作的转录机械知之甚少，以指导昼夜节律基因表达。该提案的目的是阐明哺乳动物sirtuins，III类组蛋白脱乙酰基酶（HDACS）的调节机制，在体内昼夜节律基因表达和生物节奏性。 SIRT6是一种已知的染色质相关HDAC，它指导相关基因启动子上组蛋白H3赖氨酸9的脱乙酰基化，但SIRT6并未与昼夜节律生物学有关。特别重要的是，SIRT1负责BMAL1的脱乙酰基化和调节，以及在昼夜节律启动子上H3赖氨酸9/14的脱乙酰基化。令人惊讶的是，SIRT1是一种主要位于核质中的核SIRTUIN，因此尚不清楚SIRT1的效率是否适合组蛋白靶标，还是更好地针对非源性蛋白（例如BMAL1）。假设在调节昼夜节律表达中SIRT6和SIRT1之间存在功能性相互作用，并且这些Sirtuins的亚细胞定位可能决定脱乙酰基酶活性对组蛋白与非源性靶标的效率。假设HDAC SIRT6与循环转录因子时钟和BMAL1相关，并且可能参与通过在昼夜节律启动子处脱乙酰基H3K9来调节昼夜节律基因表达，从而导致转录抑制作用和随后的CCG表达振荡。为了检验这一假设，将使用野生型和SIRT6基因敲除小鼠以及小鼠胚胎成纤维细胞（MEF）来确定SIRT6介导的对体外和体内昼夜节律基因表达的影响，以及这些作用与SIRT1有何不同。公共卫生相关性：昼夜节律是调节我们日常生理学的固有生物计时机制，此外，生物昼夜节律时钟的破坏会导致多种疾病，包括睡眠障碍，抑郁症，代谢综合征，心血管疾病和肿瘤。该提案的目的是阐明昼夜节律基因表达的调节机制，并最终在体内调节昼夜节律的调节事件。