Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network [RESEARCH ARTICLE]

Jason E. Fish, Manuel Cantu Gutierrez, Lan T. Dang, Nadiya Khyzha, Zhiqi Chen, Shawn Veitch, Henry S. Cheng, Melvin Khor, Lina Antounians, Makon-Sebastien Njock, Emilie Boudreau, Alexander M. Herman, Alexander M. Rhyner, Oscar E. Ruiz, George T. Eisenhoffer, Alejandra Medina-Rivera, Michael D. Wilson, and Joshua D. Wythe

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.

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