A transcriptional switch that controls meiosis

控制减数分裂的转录开关

基本信息

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
项目类别：
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

项目摘要

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。它们控制承诺/细胞命运决定，并将顺序叠加在分化程序上。了解转录级联如何调节非常重要，因为转录级联的调节缺陷会导致广泛的发育缺陷。了解转录级联如何调节对于理解系统水平的分化程序也至关重要。酿酒酵母（孢子形成）的减数分裂发育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，并在称为早期、中期和晚期的三大组中依次诱导。中间基因的诱导控制着减数分裂的发生，这是关键的不可逆步骤，之后不再需要诱导信号来完成该程序。中间基因的诱导也受到检查点途径的调节，该检查点途径监测程序中的先前事件（例如基因重组）是否已经完成以及依赖关系。先前的研究表明，中间启动子的诱导是由转录开关控制的，该转录开关由 Sum1 阻遏物、Ndt80 激活子和中间启动子中称为 MSE 的 DNA 元件控制。推动本提案工作的首要假设是，去除 Sum1 抑制是允许 NDT80 和减数分裂承诺表达的触发器。已完成的工作表明 Sum1 将 Sirtuin (Hst1) 招募到中间启动子，其核定位受小泛素样蛋白 (SUMO) 调节，而 Sum1 抑制的消除受细胞周期蛋白依赖性激酶和减数分裂调节-名为 Ime2 的特异性 CDK 样激酶。该提案的目标是： 1- 确定 SUM1 是否通过 NDT80 调节减数分裂前期的退出。 2- 阐明减数分裂过程中 Cdk1 和 Ime2 如何共同调节 Sum1。 3. 阐明粗线期检查点如何调节中间基因开关。 4. 阐明 SUMO 如何在减数分裂过程中调节 Sum1 细胞定位。这些研究将定义如何控制减数分裂发育的承诺，并阐明控制这种转变的类似开关特性的分子机制。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节因子协作以瞬时诱导转录级联中的基因产生新的范例。公共健康相关性：转录级联控制几乎所有分化程序。该项目将利用酿酒酵母的减数分裂发育作为模型系统，阐明信号通路如何控制转录级联。这些研究将阐明特别调节减数分裂发育和一般分化程序的新分子机制。