UNDERSTANDING MECHANISMS OF hESC SELF-RENEWAL AND CELL FATE COMMITMENT

描述（由申请人提供）：本项目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。该计划包括三个高度互动和协同的项目，建立在一个共同的生物平台上，都有科学核心支持。项目1将定义表观遗传调控和染色体结构如何受发育调控基因的细胞周期控制。初步数据表明，GI是细胞周期的“允许”阶段，此时细胞能够对分化信号做出反应。本项目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将建立PNA复制时间和全球基因组重排如何影响分化决策，以及这如何与细胞周期协调。这个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。步枪是必不可少的

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.