Gene regulatory network structure, function and evolution

基因调控网络的结构、功能和进化

• 批准号: 8845997
• 负责人: A. J. Marian Walhout
• 金额: $ 4.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845997
• 关键词: Affect; Animals; Binding; Biochemical; Biological; Biological Assay; Biological Process; Caenorhabditis elegans; Code; Complex; Congenital Disorders; DNA Binding; Data; Detection; Development; Disease; Event; Evolution; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Heat Stress Disorders; Homeostasis; Hybrids; Life; Literature; Malignant Neoplasms; Maps; Messenger RNA; Methods; Modeling; Names; Nematoda; Obesity; Organism; Oxidative Stress; Physiological; Production; Proteins; RNA Interference; Regulation; Regulator Genes; Reiterated Genes; Reporter; Resolution; Structure; System; Textbooks; Time; Tissues; Transcription factor genes; Transcriptional Regulation; Yeasts; combinatorial; human disease; insight; promoter; public health relevance; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): The transcriptional regulation of gene expression is pivotal to all biological processes. Each of our ~20,000 protein-coding genes must be expressed at the right place, time and level, as well as under the right developmental or physiological circumstances. Consequently, inappropriate gene expression is implicated in a myriad of human diseases, including congenital disorders, cancer and obesity. Transcription has been studied intensively for decades, resulting in a detailed picture of the basic biochemical mechanisms of mRNA production. However, we know little about gene regulation at a 'systems level', i.e. how TFs function together in complex gene regulatory networks (GRNs) to faithfully orchestrate the expression of large sets of genes. Our long-term goal is to comprehensively characterize the structure, function and evolution of complex metazoan GRNs to gain insights into global mechanisms of gene regulation. It is becoming increasingly clear that textbook explanations of gene regulation in which a TF binds DNA in the genome and upon doing so regulates the most proximal gene are too simplistic because many physical TF binding events lack an apparent regulatory consequence. There are several explanations for this, ranging from technical (e.g. detection limits, attribution of a bindng event to the wrong gene) to biological (e.g. redundancy between TFs, condition-dependent effects). Conversely, regulatory interactions are not necessarily due to a direct effect. For instance, TFs can function in cascades to propagate functional regulation. A major challenge is to combine physical and regulatory interactions to increase our understanding of the mechanisms of gene regulation in the context of complex multicellular organisms. Many GRN studies focus either solely on physical TF interactions, whereas others focus primarily on regulatory interactions. However, integrated GRNs that combine both are scarce and, when available are relatively small in scale. If we had high-quality, large- scale physical and regulatoy interaction data, as well as spatiotemporal and conditional gene expression data, we could build increasingly precise GRNs. Here, we will continue our studies on the nematode C. elegans to map and integrate physical and regulatory GRNs, which will help us to go beyond mapping to understanding the regulatory mechanisms of gene expression at a systems level in a complex multicellular organism.

描述（由申请人提供）： 基因表达的转录调节对于所有生物学过程都是关键的。我们约有20,000个蛋白质编码基因中的每一个都必须在正确的位置，时间和水平以及正确的发育或生理环境下表达。因此，不适当的基因表达与无数的人类疾病有关，包括先天性疾病，癌症和肥胖症。数十年来对转录进行了深入研究，从而详细介绍了mRNA产生的基本生化机制。但是，我们对“系统级别”的基因调节知之甚少，即TFS如何在复杂的基因调节网络（GRN）中共同发挥作用，以忠实地策划了大量基因的表达。我们的长期目标是全面表征复杂的后生动物GRN的结构，功能和演变，以了解对基因调节的全球机制的见解。 越来越清楚的是，基因调节的教科书解释，其中TF在基因组中结合DNA并进行调节时，最近端基因的基因过于简单，因为许多物理TF结合事件都缺乏明显的调节后果。有几种解释，从技术（例如检测极限，绑定事件归因于错误基因）到生物学（例如TFS之间的冗余，条件依赖性效应）。相反，监管相互作用不一定是由于直接影响。例如，TF可以在级联反应中运作以传播功能调节。一个主要的挑战是结合物理和调节性相互作用，以增加我们对复杂多细胞生物的基因调节机制的理解。许多GRN研究要么仅关注物理TF相互作用，而其他研究则主要集中于调节性相互作用。但是，将两者结合的集成的GRN稀缺，并且在可用的情况下，规模相对较小。如果我们有高质量的大规模物理和调节性相互作用数据，以及时空和条件基因表达数据，我们可以构建越来越精确的GRN。在这里，我们将继续对线虫秀丽隐杆线虫的研究，以绘制和整合物理和调节性GRN，这将有助于我们超越映射，以了解复杂的多细胞生物体中系统水平上基因表达的调节机制。