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.
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.
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