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）：昼夜节律时钟是一种进化保守的时间保存机制，通过调节节奏基因表达，将生物体的生理学与日常环境周期配合。由于人类生理和行为的几乎所有方面都与时钟有关，因此昼夜节律系统中的异常与多种疾病有关，包括影响50岁以上成年人的代谢综合征，因此，知道什么基因受到时钟的调节，并且有必要理解时钟障碍的机制。此外，时钟控制的转录本在昼夜节律的所有可能阶段达到峰值；但是，我们对控制阶段的基本了解。为了开始了解昼夜节律输出基因网络，我们确定了Neurospora crassa中核心时钟成分和转录因子（TF）WCC的直接目标，并在大约200个直接目标中发现了TFS的过分代表。在这些第一层TF中，ADV-1被证明具有牢固的节奏性，在时钟控制的开发中有缺陷，并且与下游代谢网络紧密相关。我们还发现，除了WCC之外，几个第一层TF与Adv-1启动子结合，并且ADV-1还馈回以与这些相同TF的启动子结合。这些相同的TF还结合并潜在地相互调节，而ADV-1的直接靶标。此外，我们对ADV-1的直接靶标的分析表明，对发育，代谢和转录控制中涉及的基因的富集富集。总之，这些数据表明，一个复杂的调节网络将WCC连接到ADV-1以及下游的发展和代谢基因。我们的数据还表明，该网络的一个功能是生成对生物学功能中鲁棒节奏至关重要的基因表达的不同时间动力学。通过结合计算和实验生物学，我们将以我们的特定目的直接测试这一想法。我们将确定上游网络如何雕刻ADV-1（AIM1）中的节奏，以及Adv-1下游网络如何产生基因表达的不同时间模式（AIM 2）。我们将结合上游和下游网络模型，以预测和验证哪些遗传变化将有选择地改变特定代谢途径的表达阶段，而特定代谢途径的表达阶段，这些途径由ADV-1节奏控制（AIM 3）。因此，这项工作的一个主要结果是开发干预措施的令人兴奋的潜力，以减少时钟破坏对人类疾病的严重影响，例如与转移工作相关的代谢综合征。