This project is focused on understanding how cell fate decisions are coordinated by cell cycle regulated changes in the epigenetic landscape and by chromosome architecture around developmentally important genes. The central hypothesis is that GI phase of the cell cycle represents a 'permissive'period when developmentally-regulated genes can be activated in response to differentiation signals. The GI phase is viewed as being permissive due to the acquisition of epigenetic modifications and a chromosome architecture that favor gene activation.
Aim 1 will investigate mechanisms that link cell cycle control with cell signaling, gene activation and cell fate specification. This will involve characterizing cell cycle dependency of transcription factor binding in GI and how this impacts gene activation. The second part of this Aim will characterize dynamic changes in histone marks at bivalent domains as cells differentiate. Finally, the model being studied in this Aim will be evaluated in other multipotent cells to determine how general the link is between cell cycle regulation and differentiation commitment.
Aim 2 is focused on understanding how bivalent domains are cell cycle regulated and what function this serves in relation to self-renewal and differentiation. Specific focus will be on mechanisms regulating H3K4 trimethylation and how histone methyltransferases are controlled in the cell cycle.
The third Aim will deal with changes in chromosome architecture at developmental genes during the cell cycle. These experiments will investigate roles for changes in chromosome architecture in relation to cell cycle dependent gene activation and its relationship with epigenetic changes at bivalent domains. Overall, this Project will establish a model explaining how differentiation decisions are linked to the cell cycle and how this is regulated by cell signaling, epigenetic controls and changes in chromosome architecture.

Public Health Relevance

Pluripotent stem cells represent a new frontier in biomedical research and have potential use in drug screening, disease modeling and regenerative medicine. This project will define mechanisms of stem cell differentiation that will contribute to their utilization for medical applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM085354-06
Application #
8641821
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
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
Type
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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