[en] The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGF-mediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis.
Disciplines :
Genetics & genetic processes
Author, co-author :
Fish, Jason E.; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Cantu Gutierrez, Manuel; Cardiovascular Research Institute, Baylor College of Medicine, Houston
Dang, Lan T.; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Khyzha, Nadiya; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Chen, Zhiqi; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Veitch, Shawn; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Cheng, Henry S.; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Khor, Melvin; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Antounians, Lina; Genetics and Genome Biology, Hospital for Sick Children, Toronto M5G 0A4, Canada.
Njock, Makon-Sébastien ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Boudreau, Emilie; Toronto General Hospital Research Institute, University Health Network, Toronto M5G 2C4, Canada.
Herman, Alexander M.; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Rhyner, Alexander M.; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Ruiz, Oscar E.; Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eisenhoffer, George T.; Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Medina-Rivera, Alejandra; Genetics and Genome Biology, Hospital for Sick Children, Toronto M5G 0A4, Canada.
Wilson, Michael D.; Genetics and Genome Biology, Hospital for Sick Children, Toronto M5G 0A4, Canada.
Wythe, Joshua D.; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
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