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

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

doi:10.1242/dev.139857

Abstract

The transmission of extracellular signals into the nucleus involves inducible transcription factors, but how different signalling 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 signalling and comprise 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. Furthermore, AP-1 is required for de novo binding of TEAD4, a transcription factor connected to Hippo signalling. Our bottom-up approach demonstrates that AP-1- and TEAD4-associated cis-regulatory elements form hubs for multiple signalling-responsive transcription factors and define the cistrome that regulates vascular and hematopoietic development by extrinsic signals.

Highlights

The hematopoietic system has been a long-standing model for general principles driving the transcriptional control of cell fate decisions
We ensured that the peptide inhibited activator protein 1 (AP-1)-driven gene activation in a luciferase assay (Fig. S1B), that its expression was tightly regulated (Fig. S1C) and that the protein was present in every cell (Fig. S1D), and demonstrated that induction of the construct blocked JUN binding to DNA in a genome-wide fashion (Fig. 1C and Fig. S1E)
Our results uncover a role for AP-1 in the establishment of the smooth muscle and vascular program from hemangioblast cells, identify the genes involved in this process and pinpoint the developmental stage at which this occurs

Summary

Introduction

The hematopoietic system has been a long-standing model for general principles driving the transcriptional control of cell fate decisions. The emergence of definitive hematopoietic stem cells (HSCs) occurs in the dorsal aorta (Medvinsky and Dzierzak, 1996), where cells of a specialized hemogenic endothelium (HE) undergo an endothelialto-hematopoietic transition (EHT), lose adherence and, as newborn HSCs, move to other sites of the embryo (Boisset et al, 2011; Eilken et al, 2009; Kissa and Herbomel, 2010; Lancrin et al, 2009) Each of these developmental transitions is regulated by an orchestrated interplay of stage-specific transcription factors (TFs). The roles of transcriptional regulators of hematopoietic differentiation are beginning to be understood, it is less clear how outside signals direct their activity and drive developmental stagespecific gene expression

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Results

Conclusion