The connectome of neural crest enhancers reveals regulatory features of signaling systems.

Cell fate commitment is controlled by cis-regulatory elements often located in remote regions of the genome. To examine the role of long-range DNA interactions in early development, we generated a high-resolution contact map of active enhancers in avian neural crest cells. This analysis uncovered a diverse repertoire of enhancers that are part of the gene regulatory network underlying specification. We found that neural crest identity is largely regulated by cis-regulatory elements that propagate signaling inputs to network components. These genomic sensors display a combination of optimal and suboptimal TCF/LEF-binding sites, which allow cells to respond to Wnt signaling in a position-dependent manner. We propose that, rather than acting as upstream activators, signaling systems feed into regulatory circuits in a hub-and-spoke architecture. These results shed light on the tridimensional organization of the neural crest genome and define how signaling systems provide progenitors with spatial cues that transform their molecular identity.