MEF2 transcription factors are key regulators of sprouting angiogenesis
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
- Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA.
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
- Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom.
- University of Liverpool
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
- University of Manchester
Angiogenesis, the fundamental process by which new blood vessels form from existing ones, depends on precise spatial and temporal gene expression within specific compartments of the endothelium. However, the molecular links between proangiogenic signals and downstream gene expression remain unclear. During sprouting angiogenesis, the specification of endothelial cells into the tip cells that lead new blood vessel sprouts is coordinated by vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (Dll4)/Notch signaling and requires high levels of Notch ligand DLL4. Here, we identify MEF2 transcription factors as crucial regulators of sprouting angiogenesis directly downstream from VEGFA. Through the characterization of a Dll4 enhancer directing expression to endothelial cells at the angiogenic front, we found that MEF2 factors directly transcriptionally activate the expression of Dll4 and many other key genes up-regulated during sprouting angiogenesis in both physiological and tumor vascularization. Unlike ETS-mediated regulation, MEF2-binding motifs are not ubiquitous to all endothelial gene enhancers and promoters but are instead overrepresented around genes associated with sprouting angiogenesis. MEF2 target gene activation is directly linked to VEGFA-induced release of repressive histone deacetylases and concurrent recruitment of the histone acetyltransferase EP300 to MEF2 target gene regulatory elements, thus establishing MEF2 factors as the transcriptional effectors of VEGFA signaling during angiogenesis.
|Number of pages||13|
|Journal||Genes & Development|
|Publication status||Published - 15 Oct 2016|
- Animals, Cells, Cultured, Embryo, Nonmammalian, Endothelial Cells/cytology, Enhancer Elements, Genetic/genetics, Gene Expression Regulation, Developmental, Histone Deacetylases/genetics, Humans, Intracellular Signaling Peptides and Proteins/genetics, MEF2 Transcription Factors/chemistry, Membrane Proteins/genetics, Mice, Neovascularization, Pathologic/genetics, Neovascularization, Physiologic/genetics, Protein Interaction Domains and Motifs, Retina/embryology, Signal Transduction, Vascular Endothelial Growth Factor A/metabolism, Zebrafish