Systems Biology of the Circadian Clock Output Network

昼夜节律时钟输出网络的系统生物学

基本信息

批准号：
9320381
负责人：
Deborah Bell-Pedersen
金额：
$ 7.17万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320381
关键词：
Adult Affect Age Amino Acids Asexual Reproduction Back Behavior Binding Biochemical Pathway Biological Models Biological Process Biology Carbon ChIP-seq Circadian Rhythms Complex Computer Simulation Computing Methodologies Data Development Disease Eukaryota Feedback Feeds Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Transcription Genome Goals Health Human Intervention Light Link Mammalian Cell Messenger RNA Metabolic Metabolic Pathway Metabolic syndrome Metabolism Modeling Molecular Mutation Neurospora Neurospora crassa Organism Outcome Output Pathway interactions Pattern Periodicity Phase Photoreceptors Physiology Proteins Regulation Regulon Reproduction spores Role Route Shapes System Systems Biology Testing Time Transcript Work circadian pacemaker genetic manipulation human disease metabolomics network models nucleotide metabolism promoter shift work stem transcription factor transcription factor USF transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The circadian clock is an evolutionarily conserved time-keeping mechanism that, through the regulation of rhythmic gene expression, coordinates the physiology of an organism with daily environmental cycles. Because virtually all aspects of human physiology and behavior are linked to the clock, abnormalities in the circadian system are associated with a wide range of diseases, including metabolic syndrome that affects up to 40% of adults over the age of 50. Thus, knowing what genes are regulated by the clock, and the mechanisms of this regulation, are necessary to understand clock-associated diseases. Furthermore, clock-controlled transcripts peak at all possible phases of the circadian cycle; however, we lack a basic understanding of what controls phase. To begin to understand the circadian output gene network, we identified the direct targets of the core clock component and transcription factor (TF) WCC in Neurospora crassa, and found an overrepresentation of TFs in the roughly 200 direct targets. Among these first tier TFs, ADV-1 was shown to be robustly rhythmic, defective in clock-controlled development, and closely linked to the downstream metabolic network. We also discovered that in addition to WCC, several first tier TFs bind to the adv-1 promoter, and that ADV-1 feeds back to bind to the promoters of these same TFs. These same TFs also bind and potentially co- regulate each other, and the direct targets of ADV-1. In addition, our analysis of the direct targets of ADV-1 revealed enrichment for genes involved in development, metabolism, and transcription control. Together, these data suggest a complex regulatory network linking WCC to ADV-1 and to downstream developmental and metabolic genes. Our data also suggest that one function of this network is to generate distinct temporal dynamics of gene expression critical to robust rhythms in biological functions. By combining computational and experimental biology, we will directly test this idea in our specific aims. We will determine how the upstream network sculpts the rhythms in ADV-1 (Aim1), and how the ADV-1 downstream network generates distinct temporal patterns of gene expression (Aim 2). We will combine the upstream and downstream network models to predict and validate which genetic changes will selectively alter the phase of expression of specific metabolic pathways that are rhythmically controlled by ADV-1 (Aim 3). As such, one major outcome of this work is the exciting potential to develop interventions to diminish the serious effects of disruption of the clock on human disease, such as metabolic syndrome associated with shift work.

描述（由申请人提供）：生物钟是一种进化上保守的计时机制，通过节律性基因表达的调节，协调生物体的生理与日常环境周期。由于人类生理和行为的几乎所有方面都与生物钟相关，因此昼夜节律系统异常与多种疾病相关，其中包括影响高达 40% 50 岁以上成年人的代谢综合征。基因受时钟调节，这种调节机制对于理解与时钟相关的疾病是必要的。此外，生物钟控制的转录本在昼夜节律周期的所有可能阶段都达到峰值。然而，我们对控制相位的因素缺乏基本的了解。为了开始了解昼夜节律输出基因网络，我们确定了粗糙脉孢菌中核心时钟组件和转录因子 (TF) WCC 的直接靶标，并发现在大约 200 个直接靶标中 TF 的比例过高。在这些第一层 TF 中，ADV-1 被证明具有很强的节律性，在时钟控制发育方面存在缺陷，并且与下游代谢网络密切相关。我们还发现，除了 WCC 之外，还有几个第一层 TF 与 adv-1 启动子结合，并且 ADV-1 反馈结合到这些相同 TF 的启动子上。这些相同的转录因子还相互结合并可能共同调节，并且是 ADV-1 的直接靶标。此外，我们对 ADV-1 直接靶标的分析揭示了参与发育、代谢和转录控制的基因的富集。总之，这些数据表明存在一个复杂的调控网络，将 WCC 与 ADV-1 以及下游发育和代谢基因联系起来。我们的数据还表明，该网络的一项功能是生成基因表达的独特时间动态，这对于生物功能的稳健节律至关重要。通过结合计算和实验生物学，我们将在我们的特定目标中直接测试这个想法。我们将确定上游网络如何塑造 ADV-1 中的节律（目标 1），以及 ADV-1 下游网络如何生成不同的基因表达时间模式（目标 2）。我们将结合上游和下游网络模型来预测和验证哪些基因变化将选择性地改变由 ADV-1 有节奏控制的特定代谢途径的表达阶段（目标 3）。因此，这项工作的一个主要成果是开发干预措施的令人兴奋的潜力，以减少时钟中断对人类疾病的严重影响，例如与轮班工作相关的代谢综合征。