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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM085354-06
Application #
8608169
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haynes, Susan R
Project Start
2008-08-01
Project End
2019-02-28
Budget Start
2014-07-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Georgia
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
Boward, Ben; Wu, Tianming; Dalton, Stephen (2016) Concise Review: Control of Cell Fate Through Cell Cycle and Pluripotency Networks. Stem Cells 34:1427-36
Foti, Rossana; Gnan, Stefano; Cornacchia, Daniela et al. (2016) Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program. Mol Cell 61:260-73
Li, Ben; Sun, Zhaonan; He, Qing et al. (2016) Bayesian inference with historical data-based informative priors improves detection of differentially expressed genes. Bioinformatics 32:682-9
Rivera-Mulia, Juan Carlos; Gilbert, David M (2016) Replication timing and transcriptional control: beyond cause and effect-part III. Curr Opin Cell Biol 40:168-78
Avery, John; Dalton, Stephen (2016) Methods for Derivation of Multipotent Neural Crest Cells Derived from Human Pluripotent Stem Cells. Methods Mol Biol 1341:197-208
Rivera-Mulia, Juan Carlos; Gilbert, David M (2016) Replicating Large Genomes: Divide and Conquer. Mol Cell 62:756-65
Wilson, Korey A; Elefanty, Andrew G; Stanley, Edouard G et al. (2016) Spatio-temporal re-organization of replication foci accompanies replication domain consolidation during human pluripotent stem cell lineage specification. Cell Cycle 15:2464-75
Singh, Amar M; Trost, Robert; Boward, Benjamin et al. (2016) Utilizing FUCCI reporters to understand pluripotent stem cell biology. Methods 101:4-10
Berger, Ryan P; Sun, Yu Hua; Kulik, Michael et al. (2016) ST8SIA4-Dependent Polysialylation is Part of a Developmental Program Required for Germ Layer Formation from Human Pluripotent Stem Cells. Stem Cells 34:1742-52
Soufi, Abdenour; Dalton, Stephen (2016) Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming. Development 143:4301-4311

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