Transcription networks in C elegans organogenesis

线虫器官发生中的转录网络

• 批准号: 7865571
• 负责人: A. J. Marian Walhout
• 金额: $ 4.34万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7865571
• 关键词: Binding; Biochemical Genetics; Biological; Caenorhabditis elegans; Computer Systems Development; DNA-Protein Interaction; Data; Data Analyses; Databases; Development; Disease; Equilibrium; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Homeostasis; Homologous Gene; Imagery; Intestines; Lead; Maps; Methods; Modeling; Nematoda; Organ; Organogenesis; Play; Property; Proteins; Regulatory Element; Repression; Research Personnel; Role; System; Tissue-Specific Gene Expression; Tissues; Transcriptional Activation; Transcriptional Regulation; Validation; Whole Organism; biological systems; computerized tools; genome-wide; insight; novel; programs; promoter; protein protein interaction; transcription factor; yeast two hybrid system

Our long-term goal is to decipher the mechanisms that control differential gene expression in metazoan systems. Differential gene expression is a major determinant in development, and misregulation of transcription can lead to numerous diseases. Although vast amounts of gene expression data are available, little is known about the mechanisms that regulate gene expression at a systems level. The expression of each gene is a balance between transcription activation and repression, governed by multiple transcription factors (TFs). Between 5-10% of metazoan genes encode TFs. Each TF regulates the expression of multiple target genes by binding both to protein partners and to target gene DMA. The multiple interactions TFs engage in, and the concerted action of multiple TFs per gene suggests that differential gene expression is the result of intricate transcription regulatory networks (TRNs) in which many TFs are functionally connected. The general aim of this proposal is to map TRNs that control intestinal development in the nematode Caenhorhabditis elegans. C. elegans intestinal development is an excellent system to understand differential gene expression because genome-wide intestinal expression data are available and because transcription regulation plays a pivotal role in this tissue. We will identify intestinal TRNs by mapping protein-DNA and protein-protein interactions involving intestinal promoters and TFs using high-throughput yeast one -and two-hybrid systems. We will generate a database for data tracking, data analysis and to make the data publicly available. To validate interactions, we will manually and computationally integrate protein interactions with available gene expression and phenotypic data. In addition, we will initiate the validation of protein interactions by experimental methods. The mapping of intestinal TRNs will reveal transcriptional mechanisms that underlie differential gene expression in intestinal development. Since this is a conserved biological program, these TRNs may provide insights into mammalian differential gene expression as well.

我们的长期目标是破译后生动物系统中控制差异基因表达的机制。差异基因表达是发育的主要决定因素，转录的失调可导致许多疾病。虽然大量的基因表达数据是可用的，很少有人知道在系统水平上调节基因表达的机制。每个基因的表达是转录激活和抑制之间的平衡，由多个转录因子（TF）控制。5-10%的后生动物基因编码TF。每个TF通过与蛋白质伴侣和靶基因DMA结合来调节多个靶基因的表达。多重交互作用TF 参与，并且每个基因的多个TF的协同作用表明，差异基因表达是复杂的转录调控网络（TRN）的结果，其中许多TF在功能上连接。 这项建议的总体目标是映射TRN控制肠道发育的线虫秀丽隐杆线虫。C.线虫肠道发育是理解差异基因表达的极好系统，因为全基因组的肠道表达数据是可用的，并且因为转录调节在该组织中起关键作用。我们将确定肠道TRN映射蛋白质-DNA和蛋白质-蛋白质相互作用，涉及肠道启动子和TF使用高通量酵母单杂交和双杂交系统。我们将建立一个数据库，用于数据跟踪、数据分析，并公开数据。为了验证相互作用，我们将手动和计算整合蛋白质相互作用与可用的基因表达和表型数据。此外，我们将启动蛋白质的验证 通过实验方法的相互作用。肠道TRN的定位将揭示 肠道发育中差异基因表达的机制。由于这是一个保守的生物学程序，这些TRN也可以提供对哺乳动物差异基因表达的见解。