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.
Pluripotent stem cells are at the forefront of a new revolution in biomedical research and serve important roles in drug screening, disease modeling and regenerative medicine. This Program is focused on the basic understanding of pluripotent stem cells so that in the future they can be more effectively and safely used in clinical applications.
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