Runt-dependent regulation of enhancer-promoter interactions

增强子-启动子相互作用的矮依赖型调节

• 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
• 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

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）：基因转录的调控对于多细胞生物体的发育至关重要，转录调控的异常通常与疾病相关。转录调控涉及顺式调控 DNA 序列，这些序列与 DNA 结合转录因子相互作用，并整合传递至启动子的信息，以控制 RNA 聚合酶合成 mRNA 转录物。真核生物中的顺式调控元件可以位于基因的上游、下游，甚至位于基因的转录区域内，并且在从果蝇延伸到人类的动物系统中，常常从转录起始位点移除许多千碱基。不同细胞类型在不同发育阶段的基因表达通过多个顺式调控元件的出现来反映，每个顺式调控元件与不同组的转录因子相互作用，整合控制信号，最终导致基因转录。尽管不同顺式元件和转录单位之间的相互作用是这种控制基因表达策略的核心，但目前对于如何调节增强子-启动子相互作用还没有明确的了解。果蝇系统中可用的工具与负责生成早期胚胎分段身体模式的途径的知识框架相结合，为研究转录调控的体内机制提供了一个有价值的模型。 Runt 是分割途径中的关键参与者，它是转录调节因子家族的创始成员，在动物发育和人类疾病中发挥着广泛的作用。该提案中的工作源于对 sloppy-paired-1 (slp1) 的研究，sloppy-paired-1 (slp1) 是分割途径中 Runt 的一个目标，为剖析转录控制机制提供了许多优势。 slp1 的初始同色异谱表达是响应于由两个不同顺式元件介导的简单组合代码而生成的。重要的是，这两个元素一起生成的模式超出了它们独立模式的加法组合的预期。解释这些元件之间功能相互作用的模型提出了 Runt 在调节这两个元件与 slp1 启动子之间的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，并包括实验询问增强子-启动子相互作用的类似调节是否有助于早期胚胎中其他基因的表达。这些结果将为 Runt 和其他转录因子的调节机制提供新的见解，这可能对理解相关蛋白质在人类发育和疾病中的作用产生广泛的影响。