Project 7: The Role of DOMINO in Regulation of Circadian Rhythms in Drosophila

项目摘要/摘要 多米诺骨牌在果蝇昼夜节律调节中的作用 生物钟协调生理、新陈代谢和行为的日常节律，使生物体能够 使地球能够预测每天的环境变化。生物钟的扰乱与许多 疾病，包括肥胖和糖尿病，心血管疾病，神经退行性疾病，甚至 癌症。研究昼夜节律的机制在基础生物学中具有深远的意义 也是为了人类的健康。在时钟控制的基因表达中，强健的周期对昼夜节律至关重要。 长期目标是了解昼夜节律基因表达是如何调控的。昼夜节律的核心 起搏器从果蝇到人类高度保守，这些机制在很大程度上是 在苍蝇身上发现的。实验室以前的研究表明，为SWR1型编码的多米诺骨牌(DOM) 核小体染色质重塑因子是一个新的果蝇时钟基因。DOM的突变体废除正常 运动活动节律。DOM蛋白通过取代DOM蛋白在转录调控中发挥关键作用 组蛋白H_2A与H_2A.V变异体。H_2A变异体与H_2A的交换影响核小体的移动 和定位，从而调节转录。此外，DOM与一种关键的昼夜节律时钟蛋白相互作用- 果蝇S2细胞的时钟(CLK)。这些发现导致了我们的假设：DOM在昼夜节律中起作用 时钟通过与CLK结合并激活时钟控制基因的转录来实现。这项建议旨在： 1)明确DOM在控制果蝇昼夜节律中的作用。2)阐明了DOM的作用机理。 昼夜节律的控制。这一提议将结合遗传学、表观遗传学、分子生物学 以及全基因组方法和行为分析来剖析DOM的作用和功能 苍蝇生物钟的机制。生物钟的守时机制从苍蝇到苍蝇都是高度保守的。 人类。这些研究有望通过染色质重塑揭示生物钟的新机制。 并将促进人们对生物钟的理解。这些发现可能会对以下方面产生重大影响 了解人类的生物钟，以及与染色质重塑和 生物钟被打乱。

PROJECT SUMMARY/ABSTRACT The Role of DOMINO in Regulation of Circadian Rhythms in Drosophila Circadian clocks coordinate daily rhythms in physiology, metabolism, and behavior to enable organism on Earth to anticipate daily environmental changes. Disruptions of circadian clocks have been linked to many diseases, including obesity and diabetes, cardiovascular diseases, neurodegenerative diseases, and even cancers. Studying the mechanisms underlying circadian rhythms has profound significance in basic biology and for human health. Robust cycling in clock controlled gene expression is critical for circadian timekeeping. The long-term goal is to understand how circadian gene expressions are regulated. The core of the circadian pacemaker is highly conserved from Drosophila to human, and these mechanisms were in great part discovered in flies. Previous studies in the lab indicate that domino (dom), which encodes for the SWR1-type nucleosome chromatin remodeling factor, is a novel clock gene in Drosophila. Mutants of dom abolish normal locomotor activity rhythms. DOM protein plays a critical role in transcriptional regulation by replacing the histone H2A with the H2A.V variant. An exchange of the H2A variant with H2A affects nucleosome mobility and positioning, thus regulating transcription. Furthermore, DOM interacts with a critical circadian clock protein- CLOCK (CLK) in Drosophila S2 cells. These findings lead to our hypothesis that DOM acts in the circadian clock through binding to CLK and activating the transcription of clock-controlled genes. This proposal seeks to: 1) define the role of DOM in the control of Drosophila circadian rhythms. 2) elucidate the mechanism of DOM in the control of circadian rhythms. This proposal will combine a set of genetics, epigenetics, molecular biology and genome wide approaches as well as behavior assays to dissect the role of DOM and its function mechanism in flies circadian clock. The mechanisms of circadian timekeeping are highly conserved from fly to human. These studies will hopefully reveal a novel mechanism of the circadian clock by chromatin remodeling and will advance understanding of circadian clocks. These findings will likely have significant implications for understanding human circadian clock, as well as disorders related to defects of chromatin remodeling and disruption of circadian clock.