PUBLICATION

Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network

Authors
Fish, J.E., Cantu Gutierrez, M., Dang, L.T., Khyzha, N., Chen, Z., Veitch, S., Cheng, H.S., Khor, M., Antounians, L., Njock, M.S., Boudreau, E., Herman, A.M., Rhyner, A.M., Ruiz, O.E., Eisenhoffer, G.T., Medina-Rivera, A., Wilson, M.D., Wythe, J.D.
ID
ZDB-PUB-170706-9
Date
2017
Source
Development (Cambridge, England)   144: 2428-2444 (Journal)
Registered Authors
Boudreau, Emilie, Cheng, Henry, Dang, Lan, Fish, Jason E., Njock, Sebastien, Wythe, Joshua
Keywords
Angiogenesis, ETS factor, Endothelial cell, Enhancer, Genome editing, Human, Mouse, Transcription, Zebrafish
MeSH Terms
  • Cattle
  • Animals
  • Gene Regulatory Networks/drug effects*
  • Male
  • Vascular Endothelial Growth Factor A/pharmacology*
  • Transcriptional Regulator ERG/metabolism
  • Enhancer Elements, Genetic/genetics
  • Zebrafish/embryology
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Transcription, Genetic/drug effects*
  • Gene Expression Regulation, Developmental/drug effects
  • E1A-Associated p300 Protein/metabolism*
  • Introns/genetics
  • Gene Expression Regulation/drug effects*
  • Extracellular Signal-Regulated MAP Kinases/metabolism*
  • Mice
  • Human Umbilical Vein Endothelial Cells/drug effects
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Humans
  • Neovascularization, Physiologic/genetics
  • MAP Kinase Signaling System/drug effects
  • Female
(all 22)
PubMed
28536097 Full text @ Development
Abstract
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ci5TgTransgenic Insertion
    s843TgTransgenic Insertion
      s940TgTransgenic Insertion
        um14TgTransgenic Insertion
          y7TgTransgenic Insertion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            No data available
            Fish
            No data available
            Antibodies
            No data available
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            mCherryEFGmCherry
            VenusEFGVenus
            1 - 3 of 3
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            Mapping
            No data available
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            Citation
            Fish, J.E., Cantu Gutierrez, M., Dang, L.T., Khyzha, N., Chen, Z., Veitch, S., Cheng, H.S., Khor, M., Antounians, L., Njock, M.S., Boudreau, E., Herman, A.M., Rhyner, A.M., Ruiz, O.E., Eisenhoffer, G.T., Medina-Rivera, A., Wilson, M.D., Wythe, J.D. (2017) Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network. Development (Cambridge, England). 144:2428-2444.