title: Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate.
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.
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Nadine
authors: N
authors: Obier
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Pierre
authors: P
authors: Cauchy
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Salam A
authors: SA
authors: Assi
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Jane
authors: J
authors: Gilmour
authors: CRUK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors: Michael
authors: M
authors: Lie-A-Ling
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Monika
authors: M
authors: Lichtinger
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Maarten
authors: M
authors: Hoogenkamp
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Laura
authors: L
authors: Noailles
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
authors: Peter N
authors: PN
authors: Cockerill
authors: CRUK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors: Georges
authors: G
authors: Lacaud
authors: CRUK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors: Valerie
authors: V
authors: Kouskoff
authors: Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK c.bonifer@bham.ac.uk.
authors: Constanze
authors: 0000-0002-4267-0825
authors: C
authors: Bonifer
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000091262:TEA Domain Transcription Factors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051696:Activating Transcription Factors; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000091262:TEA Domain Transcription Factors; C101204:Tead4 protein, mouse; D018808:Transcription Factor AP-1; D014157:Transcription Factors
keywords: AP-1; ESC differentiation; Hematopoietic specification; Hippo signalling; Signalling hubs; TEAD4