A transcriptional switch that controls meiosis

控制减数分裂的转录开关

• 批准号: 7946081
• 负责人: EDWARD P WINTER
• 金额: $ 30.22万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7946081
• 关键词: Binding; Biological Models; Biological Process; Cell Cycle Checkpoint; Cells; Chromatin; Cyclin-Dependent Kinases; DNA; Defect; Dependency; Development; Elements; Event; Excision; Genes; Genetic Recombination; Germ Cells; Goals; Growth; Indium; Mediating; Meiosis; Middle Promoters; Modification; Molecular; Monitor; Names; Nuclear; Pathway interactions; Phosphotransferases; Play; Property; Prophase; Publishing; Recruitment Activity; Reporting; Repression; Reproduction spores; Role; Saccharomyces cerevisiae; Signal Pathway; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Switch Genes; System; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Regulation; Ubiquitin; Ubiquitin Like Proteins; Work; Yeasts; base; biological systems; cell type; feeding; gene induction; insight; mutant; paralogous gene; programs; promoter; public health relevance; research study; response

DESCRIPTION (provided by applicant): Transcriptional cascades are ubiquitous in differentiating systems. They control commitment/cell fate decisions and superimpose order on differentiation programs. Understanding how transcriptional cascades are regulated is important since defective regulation of transcriptional cascades cause a broad spectrum of developmental defects. Understanding how transcriptional cascades are regulated is also critical for understanding differentiation programs at the systems level. Meiotic development in the yeast Saccharomyces cerevisiae (sporulation) is an outstanding model system for studying molecular mechanisms that regulate differentiation. Meiosis-specific genes are repressed during vegetative growth and sequentially induced in three broad groups termed early, middle, and late. The induction of middle genes controls commitment to meiosis, the key irreversible step after which the inducing signal is no longer needed to complete the program. The induction of middle genes is also regulated by a checkpoint pathway that monitors whether preceding events in the program (such as genetic recombination) has been completed and by dependency relationships. Previous studies have shown that the induction of middle promoters is controlled by a transcriptional switch that is controlled by the Sum1 repressor, the Ndt80 activator, and DNA elements in middle promoters termed MSEs. The overarching hypothesis motivating the work in this proposal is that the removal of Sum1 repression is the trigger that permits the expression of NDT80 and meiotic commitment. Completed work has shown that Sum1 recruits a sirtuin (Hst1) to middle promoters, that its nuclear localization is regulated by the small ubiquitin like protein (SUMO), and that the removal of Sum1 repression is regulated by cyclin-dependent kinase and by a meiosis-specific CDK-like kinase named Ime2. The goals of the proposal are: 1- Establish whether SUM1 regulates exit from meiotic prophase through NDT80. 2- Elucidate how Cdk1 and Ime2 co-regulate Sum1 during meiosis. 3. Elucidate how the pachytene checkpoint regulates the middle gene switch. 4. Elucidate how SUMO regulates Sum1 cellular localization during meiosis. These studies will define how commitment to meiotic development is controlled and elucidate molecular mechanisms that control the switch-like properties of this transition. These studies are expected to generate new paradigms for how CDKs and cell-type specific CDK-like kinases collaborate with transcriptional regulators to transiently induce genes in transcriptional cascades. PUBLIC HEALTH RELEVANCE: Transcriptional cascades control virtually all differentiation programs. This project will elucidate how signaling pathways control transcriptional cascades using meiotic development in the yeast Saccharomyces cerevisiae as a model system. These studies will elucidate new molecular mechanisms that regulate meiotic development in particular and differentiation programs in general.

描述（由申请人提供）：转录级联在分化系统中普遍存在。它们控制着定型/细胞命运的决定，并控制着分化程序的顺序。理解转录级联是如何调节的是重要的，因为转录级联的缺陷调节导致广泛的发育缺陷。了解转录级联如何调节对于了解系统水平的分化程序也至关重要。酵母酿酒酵母减数分裂发育（孢子形成）是研究调节分化的分子机制的杰出模型系统。减数分裂特异性基因在营养生长过程中受到抑制，并在三个广泛的群体中依次诱导，称为早期，中期和晚期。中间基因的诱导控制减数分裂的承诺，这是一个关键的不可逆步骤，在此之后，不再需要诱导信号来完成程序。中间基因的诱导也受到检查点途径的调节，该途径监测程序中的先前事件（如遗传重组）是否已经完成，并受到依赖关系的调节。先前的研究表明，中间启动子的诱导是由一个转录开关控制的，该转录开关由Sum 1阻遏物、Ndt 80激活物和称为MSE的中间启动子中的DNA元件控制。在这项提议中，最重要的假设是Sum 1抑制的消除是允许NDT 80表达和减数分裂定型的触发器。已完成的工作表明，Sum 1招募sirtuin（Hst 1）到中间启动子，其核定位由小泛素样蛋白（SUMO）调节，并且Sum 1抑制的去除由细胞周期蛋白依赖性激酶和命名为Ime 2的减数分裂特异性CDK样激酶调节。该提案的目标是：1-确定SUM 1是否通过NDT 80调节退出减数分裂前期。2-阐明Cdk 1和Ime 2在减数分裂过程中如何共同调节Sum 1。3.阐明粗线期检查点如何调节中间基因开关。4.阐明SUMO在减数分裂过程中如何调节Sum 1的细胞定位。这些研究将确定如何承诺减数分裂的发展是控制和阐明控制这种转变的开关样性质的分子机制。这些研究有望为CDK和细胞类型特异性CDK样激酶如何与转录调控因子合作以瞬时诱导转录级联中的基因产生新的范例。 公共卫生相关性：转录级联控制几乎所有的分化程序。本计画将以酿酒酵母的减数分裂为模型系统，探讨信号通路如何控制转录级联反应。这些研究将阐明新的分子机制，特别是调节减数分裂的发展和一般的分化程序。