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.
- Received May 16, 2016.
- Accepted October 10, 2016.
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