Runt-dependent regulation of enhancer-promoter interactions

增强子-启动子相互作用的矮依赖型调节

基本信息

批准号：
8389727
负责人：
John Peter Gergen
金额：
$ 2.17万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389727
关键词：
Accounting Animals Binding Sites Biochemical Biological Assay Blastoderm Body Patterning Cells Chromatin Code DNA DNA Binding DNA Sequence DNA-Directed RNA Polymerase Development Disease Distal Drosophila genus Elements Embryo Embryonic Development Enhancers Eukaryota Family Fushi tarazu transcription factors Gene Expression Gene Expression Regulation Genes Genetic Genetic Enhancer Element Genetic Transcription Genomics Human Development Imaging Techniques In Situ Indium Individual Knowledge Laboratories Mediating Messenger RNA Modeling Molecular Molecular Conformation Mutate Organism Output Pathway interactions Pattern Property Protein Family Proteins Regulation Regulatory Element Reporter Genes Research Response Elements Role Signal Transduction Site Staging Structure System Testing Transcript Transcription Factor 3 Transcription Initiation Site Transcriptional Regulation Transgenic Organisms Work base cell type combinatorial homeodomain human disease in vivo insight man member novel promoter research study response tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The regulation of gene transcription is critical for the development of multi-cellular organisms and aberrations in transcriptional regulation are frequently associated with disease. The regulation of transcription involves cis-regulatory DNA sequences that interact with DNA-binding transcription factors and integrate information that is communicated to the promoter to control the synthesis of mRNA transcripts by RNA polymerase. Cis-regulatory elements in eukaryotes can be located upstream, downstream, or even within the transcribed region of a gene, and in animal systems extending from fruit fly to man are frequently many kilobases removed from the transcription start site. The expression of genes in different cell types at different stages of development is reflected by the occurrence of multiple cis-regulatory elements, each of which interacts with different sets of transcription factors to integrate the control signals that eventually result in gene transcription. Although interactions between different cis-elements and the transcription unit are central to this strategy of controlling gene expression, there is as of yet no clear understanding of how enhancer-promoter interactions are regulated. The tools available in the Drosophila system in conjunction with the framework of knowledge on the pathway responsible for generating the segmented body pattern of the early embryo provide a valuable model for investigating the in vivo mechanisms of transcription regulation. A key player in the segmentation pathway is Runt, the founding member of a family of transcriptional regulators with wide-ranging roles in animal development and human disease. The work in this proposal emanates from studies on sloppy-paired-1 (slp1), a target of Runt in the segmentation pathway that offers numerous advantages for dissecting transcriptional control mechanisms. The initial metameric expression of slp1 is generated in response to a simple combinatorial code that is mediated by two distinct cis-elements. Importantly, the two elements together generate a pattern beyond what is expected from the additive combination of their independent patterns. A model accounting for the functional interplay between these elements proposes a novel role for Runt in regulating interactions between these two elements and the slp1 promoter. The proposed work further investigates the molecular basis for this regulatory phenomenon and includes experiments asking whether a similar regulation of enhancer-promoter interactions contributes to the expression of other genes in the early embryo. The results will provide new insights on the mechanisms of regulation by Runt and other transcription factors that are likely to have widespread implications for understanding the roles of related proteins in human development and disease.

描述（由申请人提供）：基因转录的调节对于多细胞生物的发展至关重要，转录调控中的像差通常与疾病有关。转录的调节涉及与DNA结合转录因子相互作用的顺式调节DNA序列，并将传达给启动子传达的信息整合，以控制RNA聚合酶对mRNA转录的合成。真核生物中的顺式调节元素可以位于基因的抄录区域的上游，下游甚至内部，而在从果蝇到人的动物系统中，经常从转录起始位点移走许多千叠酶。多个顺式调节元件的发生反映了不同细胞类型的基因在不同细胞类型中的表达，每种元件都与不同的转录因子集相互作用，以整合最终导致基因转录的控制信号。尽管不同的顺式元素与转录单元之间的相互作用是控制基因表达策略的核心，但尚无清楚地了解增强子促进剂的相互作用。果蝇系统中可用的工具以及负责产生早期胚胎分段的身体模式的知识框架为研究转录调节的体内机制提供了有价值的模型。分割途径中的关键参与者是Runt，Runt是转录调节器家族的创始成员，在动物发育和人类疾病中具有广泛的作用。该提案中的工作源自对草率生成1（SLP1）的研究，这是分割途径中Runt的目标，该途径为剖析转录控制机制提供了许多优势。 SLP1的初始元表表达是根据由两个不同的顺式元素介导的简单组合代码而生成的。重要的是，这两个元素共同产生了一个模式，超出了其独立模式的添加组合的期望。这些元素之间功能相互作用的模型提出了Runt在调节这两个元素与SLP1启动子之间相互作用中的新作用。拟议的工作进一步研究了这种调节现象的分子基础，包括实验，询问相似的增强子促销相互作用的调节是否有助于早期胚胎中其他基因的表达。结果将为Runt和其他转录因子的调节机制提供新的见解，这些因素可能对了解相关蛋白在人类发育和疾病中的作用具有广泛影响。