Journal
DEVELOPMENT
Volume 144, Issue 13, Pages 2428-2444Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.146050
Keywords
Endothelial cell; Transcription; Enhancer; Angiogenesis; Genome editing; ETS factor; Zebrafish; Mouse; Human
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP-119506]
- Leaders Opportunity Fund/Canada Foundation for Innovation [26422]
- Ontario Ministry of Research and Innovation
- University of Toronto's Medicine by Design initiative
- Canada First Research Excellence Fund
- Toronto General Hospital Research Institute
- Natural Sciences and Engineering Research Council of Canada
- Vascular Network Scholar Award (CIHR)
- Ontario Graduate Student award
- Natural Sciences and Engineering Research Council of Canada (NSERC) [4361942013]
- Alexander Graham Bell Canada Graduate Scholarship
- CONACYT [269449, 203853]
- Programa de Apoyo a Proyectos de investigacion e innovacion tecnologica - Universidad Nacional Autonoma de Mexico (PAPII-TUNAM) [IA206517]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RR140077]
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- CVRI at Baylor College of Medicine
- Caroline Wiess Law Fund
- Curtis Hankamer Basic Research Fund
- ARCO Foundation Young Teacher-Investigator
- American Heart Association [16GRNT31330023]
- CIHR
- CIHR STAGE
- National Institutes of Health [CA125123, RR024574]
- Molecular Physiology of the Cardiovascular System Training Grant, National Institutes of Health [T32HL07676]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available