Pluripotency is a critical model for understanding fundamental principles of cell fate specification. This process makes selective use of enhancers, regulatory elements that facilitate the transcription of cell-type specific genes. Increased understanding of the molecular events that regulate enhancer activity, particularly under developmental contexts, will provide important insights into congenital diseases that occur with their dysregulation.

The chromatin state at enhancers is characterized by the presence of the histone variant, H3.3, and recruitment of the CBP/p300 family of transcriptional co-activators. Our recent studies demonstrate that H3.3 deposition at enhancers allows for variant-specific phosphorylation that stimulates p300 acetyltransferase activity towards its substrate histone H3 lysine 27 (H3K27ac) in mouse embryonic stem cells (ESCs).

The goals of this arm of our research program are to:

• Determine how H3.3 phosphorylation stimulates p300 activity in ESCs

• Understand the role of CBP/p300 co-activators at specific developmental enhancers

• Study how developmental metabolism regulates CBP/p300 enzymatic activity

• Determine how H3.3 and CBP/p300 function to promote transcription during pre-implantation development