A transcriptional switch that controls meiosis

描述(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很重要，因为转录级联的缺陷调控会导致广泛的发育缺陷。了解转录级联是如何调控的，对于在系统水平上理解分化程序也是至关重要的。酿酒酵母的减数分裂发育(孢子形成)是研究调控分化的分子机制的一个优秀的模式系统。减数分裂特异基因在营养生长过程中被抑制，并在三个广泛的群体中依次诱导，即早期、中期和晚期。中间基因的诱导控制着减数分裂的承诺，这是关键的不可逆转的步骤，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检查点通路的调节，该通路监测程序中之前的事件(如基因重组)是否已经完成，并受到依赖关系的调节。以前的研究表明，中间启动子的诱导是由转录开关控制的，该开关由Sum1抑制因子、Ndt80激活子和中间启动子中的DNA元件控制，称为MSE。该提案中激励这项工作的首要假设是，Sum1抑制的消除是允许NDT80表达和减数分裂承诺的触发因素。已完成的工作表明，Sum1在中间启动子中招募sirtuin(Hst1)，其核定位受小泛素样蛋白(SUMO)调节，Sum1抑制的去除受细胞周期蛋白依赖的激酶和减数分裂特异的CDK样激酶IME2的调节。该提案的目标是：1-确定SUM1是否调节从减数分裂前期到NDT80的退出。2-阐明CDK1和IME2如何在减数分裂过程中共同调节Sum1。3.阐明粗线期检查点是如何调控中间基因开关的。4.阐明SUMO在减数分裂过程中对Sum1细胞定位的调控。这些研究将定义如何控制对减数分裂发育的承诺，并阐明控制这种转变的开关性质的分子机制。这些研究有望为CDK和细胞型特异性CDK样激酶如何与转录调控因子合作在转录级联中瞬时诱导基因产生新的范式。 与公共健康相关：转录级联反应控制着几乎所有的分化计划。本项目将以酿酒酵母的减数分裂发育为模型系统，阐明信号通路如何控制转录级联反应。这些研究将阐明调控减数分裂发育的新的分子机制，特别是一般的分化程序。

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.