Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

The transmission of extracellular signals into the nucleus involves inducible transcription factors, but how different signaling pathways act in a cell type-specific fashion is poorly understood. Here, we studied the regulatory role of the AP-1 transcription factor family in blood development using embryonic stem cell differentiation coupled with genome-wide transcription factor binding and gene expression analyses. AP-1 factors respond to MAP kinase signaling and are comprised of dimers of FOS, ATF and JUN proteins. To examine genes regulated by AP-1 and to examine how it interacts with other inducible transcription factors we abrogated its global DNA-binding activity using a dominant negative FOS peptide. We show that FOS and JUN bind to and activate a specific set of vascular genes and that AP-1 inhibition shifts the balance between smooth muscle and hematopoietic differentiation towards blood. Further, AP-1 is required for de novo binding of TEAD4, a transcription factor connected to Hippo signaling. Our bottom-up approach demonstrates that AP-1 and TEAD4 associated cis-regulatory elements comprise hubs for multiple signaling responsive transcription factors and defines the cistrome regulating vascular and hematopoietic development by extrinsic signals.