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

Nadine Obier, Pierre Cauchy, Salam A Assi, Jane Gilmour, Michael Lie-A-Ling, Monika Lichtinger, Maarten Hoogenkamp, Laura Noailles, Peter N Cockerill, Georges Lacaud, Valerie Kouskoff, Constanze Bonifer

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)
376 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)4324-4340
JournalDevelopment (Cambridge)
Volume143
Early online date17 Oct 2016
DOIs
Publication statusPublished - 2016

Keywords

  • AP-1
  • signaling hubs
  • ESC differentiation
  • TEAD4
  • Hippo signaling
  • hematopoietic specification

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