UNDERSTANDING MECHANISMS OF hESC SELF-RENEWAL AND CELL FATE COMMITMENT

描述(由申请人提供)：该计划的主要主题将是定义细胞周期如何协调表观遗传事件和染色体重塑，以及这如何影响多能性和细胞命运决定。该计划包括建立在一个共同生物平台上的三个高度互动和协同的项目，所有这些项目都得到了科学核心的支持。项目1将定义表观遗传调节和染色体结构如何受制于发育调节基因的细胞周期控制。初步数据表明，当细胞能够对分化信号做出反应时，GI是细胞周期的一个“允许”阶段。本项目中提出的实验将定义一种将细胞周期转变与分化途径激活联系起来的机制。项目2将确定PNA复制时机和全球基因组重排如何影响分化决定，以及这如何与细胞周期相协调。该项目的第二个重点将是了解RIFL在染色体组织和细胞命运决定中的作用。RIFL对于建立 正确的复制计时程序，很可能在分化过程中的染色体重组中发挥关键作用。项目3将研究绝缘体如何在细胞周期中控制染色体组织，然后将研究在多能细胞中形成拓扑域的机制。最后，本项目将描述多能细胞分化过程中绝缘体在基因组组织中的作用。这三个项目紧密相连，并以互补的方法处理重叠的生物学主题--这将在该计划内产生高度的协同效应。所有项目都将大量使用干细胞核心(核心A)、生物信息学核心(核心B)，并将得到行政核心(核心C)的支持。核心在支持在计划项目框架外是不可行的活动方面具有关键作用。该方案还利用资源，通过支持试点项目和协作来提高协同效应和临界质量。

DESCRIPTION (provided by applicant): The overarching theme of this Program will be to define how the cell cycle coordinates epigenetic events and chromosome remodeling and how this impacts on pluripotency and cell fate decisions. The Program comprises three highly interactive and synergistic projects built on a common biological platform, all supported by scientific cores. Project 1 will define how epigenetic regulation and chromosome architecture are subject to cell cycle control at developmentally-regulated genes. Preliminary data indicates that GI is a 'permissive' phase of the cell cycle when cells are capable of responding to differentiation signals. Experiments proposed in this Project will define a mechanism linking cell cycle transition to the activation of differentiation pathways. Project 2 will establish how PNA replication timing and global genome rearrangements impact differentiation decisions and how this is coordinated with the cell cycle. A second focus of this project will be to understand the role of Rifl in chromosome organization and cell fate decisions. Rifl is essential for establishing the correct replication timing program and is likely to have critical roles in chromosome reorganization during differentiation. Project 3 will look at how 'insulators' control chromosome organization during the cell cycle and then will investigate mechanisms by which topological domains are formed in pluripotent cells. Finally, this Project will characterize the role of insulators in genome organization as pluripotent cells differentiate. The three Projects are tightl interconnected and address overlapping biological themes with complementary approaches - this will create a high level of synergy within the Program. All Projects will heavily utilize the Stem Cell Core (Core A), the Bioinformatics Core (Core B), and will be supported by an Administrative Core (Core C). The Cores have key roles in supporting activities that would not be feasible outside the framework of a Program Project. The Program also leverages resources to increase synergy and critical mass through support of Pilot Projects and collaborations.