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A transcriptional switch that controls meiosis

控制减数分裂的转录开关

基本信息

批准号：
8515460
负责人：
EDWARD P WINTER
金额：
$ 29.62万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515460
关键词：
Beryllium 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。它们控制着承诺/细胞命运的决定，并将秩序叠加在分化程序上。了解转录级联是如何调控的是很重要的，因为转录级联的调控缺陷会导致广泛的发育缺陷。理解转录级联是如何被调控的对于理解系统水平上的分化程序也是至关重要的。酵母减数分裂发育是研究调控分化的分子机制的一个杰出的模式系统。减数分裂特异性基因在营养生长过程中被抑制，并依次在早期、中期和晚期三大类中被诱导。中间基因的诱导控制着减数分裂的承诺，这是关键的不可逆步骤，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一个转录开关控制的，该转录开关由Sum1抑制子、Ndt80激活子和中间启动子中称为mse的DNA元件控制。这项研究的主要假设是，Sum1抑制的去除是NDT80表达和减数分裂的触发因素。已完成的工作表明，Sum1将sirtuin （Hst1）招募到中间启动子，其核定位由小泛素样蛋白（SUMO）调节，Sum1抑制的去除由周期蛋白依赖性激酶和减数分裂特异性cdk样激酶Ime2调节。该提案的目标是：1-确定SUM1是否通过NDT80调控减数分裂前期的退出。2-阐明Cdk1和Ime2在减数分裂过程中如何共同调控Sum1。3. 阐明粗线素检查点如何调控中间基因开关。4. 阐明SUMO在减数分裂过程中如何调控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合作在转录级联中瞬时诱导基因产生新的范例。