Gene Regulatory Codes and Signal/Regulatory Element Interactions in IME2

IME2 中的基因调控代码和信号/调控元件相互作用

• 批准号: 7254454
• 负责人: SAUL M HONIGBERG
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254454
• 关键词: Acetates; Affect; Alleles; Biological Assay; Code; Complex; Data; Defect; Diabetes Mellitus; Disease; Etiology; Gene Expression; Genes; Genetic Epistasis; Genetic Models; Genetic Transcription; Genome; Genomics; Glucose; Health; Human; LacZ Genes; Lead; Logic; Malignant Neoplasms; Measures; Meiosis; Mutagenesis; Nitrogen; Nucleic Acid Regulatory Sequences; Nutritional; Organism; Output; Parkinson Disease; Pathway interactions; Phenotype; Point Mutation; Regulator Genes; Regulatory Element; Research; Saccharomyces cerevisiae; Saccharomycetales; Scanning; Signal Transduction; System; Testing; Transcriptional Regulation; Yeasts; chromatin immunoprecipitation; human disease; mutant; promoter

DESCRIPTION (provided by applicant): The long-term objective of the Honigberg lab is to identify the mechanisms by which yeast regulate their transition into the meiotic pathway. This system presents a unique opportunity to study fundamental mechanisms by which diverse signals are integrated to control cellular fates. The first specific aim of the proposal is to determine the gene regulatory code for IME2, i.e. to identify all of the regulatory elements that control expression of this gene and the signal or signals to which they respond. This aim will be achieved through extensive mutagenesis of the promoter of a genomic ime2-lacZ allele, followed by assaying each ime2-x-lacZ mutant under all combinations of the three major signals that regulate this gene. Analysis of this combination of sequence and expression data will reveal the logic circuits underlying the gene regulatory code. The second aim of the proposal is to identify interactions between IME2 regulatory elements. The first part of this aim will be accomplished by measuring the effect of selected ime2-x-lacZ alleles on association of Ime1p and Rpd3p with the URS1 regulatory element of IME2. The second part of this aim will be to determine the interactions between IME2 regulatory elements that have shared functions. This will be accomplished by epistasis (double mutant analysis). Because the proposed research will result in the first complete description of a eukaryotic gene regulatory code, accomplishing this project provides a framework for understanding regulatory codes in other genes, including genes whose altered expression results in human disease. Defects in the regulation of transcription have profound effects on human health, affecting such diverse diseases as diabetes, cancer, and Parkinson's. Because the mechanism of transcriptional regulation is complex and still poorly understood, studying transcriptional regulation in a model genetic organism, the budding yeast S. cerevisiae, can lead to fundamental discoveries that advance our understanding of the etiology of these diseases.

描述（由申请人提供）：Honigberg Lab的长期目标是确定酵母调节其过渡到减数分裂途径的机制。该系统为研究基本机制提供了一个独特的机会，通过这些机制将各种信号集成以控制细胞命运。该提案的第一个具体目的是确定IME2的基因调节代码，即确定控制该基因表达表达的所有调节元素以及它们响应的信号或信号。通过对基因组IME2-LACZ等位基因的启动子进行广泛的诱变，将实现这一目标，然后在调节该基因的三个主要信号的所有组合下测定每个IME2-X-LACZ突变体。对序列和表达数据组合的分析将揭示基因调节代码的逻辑电路。该提案的第二个目的是确定IME2调节要素之间的相互作用。该目标的第一部分将通过测量选定的IME2-X-LacZ等位基因对IME1P和RPD3P与IME2的URS1调节元件的关联的影响来实现。该目标的第二部分是确定具有共享功能的IME2调节元素之间的相互作用。这将通过上毒（双重突变分析）来实现。由于拟议的研究将导致对真核基因调节守则的首次完整描述，因此完成该项目为理解其他基因的调节代码提供了一个框架，其中包括其表达改变导致人类疾病的基因。调节转录的缺陷对人类健康具有深远的影响，影响了糖尿病，癌症和帕金森氏症等各种疾病。由于转录调控的机制是复杂的，但仍然很少理解，因此研究了模型遗传生物中的转录调节，酿酒酵母酿酒酵母可能会导致基本发现，从而促进我们对这些疾病病因的理解。