Through integrative analysis and investigative experimentation, this work identified the first functional link between developmental competence and the poised enhancer state. Our results demonstrated that a poised enhancer landscape, specific to descendant lineages such as the liver, lung, and pancreas, is established at the gut tube stage of stem cell differentiation. Interestingly, these poised enhancers are predictive of developmental competence, i.e., the ability of gut tube cells to respond to each organ’s inductive cues. This work is the first to show that the epigenome can provide instructions for directed stem cell differentiation toward liver, lung, and pancreas. Significantly, it provides an epigenetic mechanism for developmental competence, and an explanation for why broadly-expressed signaling molecules are able to evoke cell-type-specific responses during development.
Although the link between epigenetic regulation at enhancers and lineage identity is now accepted, little is known about the mechanisms that construct this enhancer epigenome during human development. We have begun to address by investigating how the pancreatic enhancer landscape is assembled during pancreatic induction of hPSCs. Interestingly, our data suggests a multi-layered model whereby the pioneer transcription factors (TFs) FOXA1 and 2 play multiple roles to coordinate the interplay between developmental signals, histone modifications, and chromatin accessibility. This work addresses the larger biological question of how a core set of developmental TFs can play multiple roles to regulate cell fate by identifying and characterizing novel functions for FOXA1/2.