The mystery of differentiation: exploring the link between enhancer priming and cell cycle in ventral foregut stem cells

Pluripotent stem cell differentiation to disease targeted cell types has historically produced poor or inconsistent outcomes.

The Brickman lab recently suggested that pausing differentiation, allowing cells to grow, and catch up at the level of the enhancer network, leads to improved differentiation.

In particular, the Brickman lab has demonstrated that expansion of endoderm at the ventral foregut stage (VFG) increases the efficiency and efficacy of pancreatic endocrine differentiation.

The mechanism by which this occurs is unknown, but it involves the re-equilibration of enhancer networks and rearrangements in the cell cycle.

I hypothesise that these two processes are tightly connected and to address cause and effects and understand the nature of this link, I will focus on how FOXA1, a factor required for expansion-specific pancreatic enhancer reorganization, acts to couple growth to genome rearrangement, how it interacts with the REST/CoREST/KBTBD4 complex to facilitate enhancer commissioning/decommissioning and finally whether proliferation-induced alterations to specific cell cycles phases drive this enhancer reconfiguration.

The results of this project will significantly impact on regenerative medicine research as they will help formulating a differentiation protocol that produces in a more efficient way pancreatic endoderm and pancreatic endocrine cells.

Although this fellowship exploits pancreatic differentiation as a model, its implications are broad, as a role of proliferation in preparing appropriate transcriptional responses for differentiating cells would represent a new paradigm for the link between growth and lineage specification.