MEF2 transcription factors are key regulators of sprouting angiogenesis
- Natalia Sacilotto1,9,
- Kira M. Chouliaras1,9,
- Leonid L. Nikitenko1,8,
- Yao Wei Lu2,
- Martin Fritzsche1,
- Marsha D. Wallace1,
- Svanhild Nornes1,
- Fernando García-Moreno3,
- Sophie Payne1,
- Esther Bridges4,
- Ke Liu5,
- Daniel Biggs6,
- Indrika Ratnayaka1,
- Shane P. Herbert7,
- Zoltán Molnár3,
- Adrian L. Harris4,
- Benjamin Davies6,
- Gareth L. Bond1,
- George Bou-Gharios5,
- John J. Schwarz2 and
- Sarah De Val1
- 1Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
- 2Center for Cardiovascular Sciences, Albany Medical College, Albany, New York 12208, USA;
- 3Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
- 4Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom;
- 5Institute of Aging and Chronic Disease, University of Liverpool, Liverpool L7 8TX, United Kingdom;
- 6The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
- 7Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
- Corresponding author: sarah.deval{at}ludwig.ox.ac.uk
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↵9 These authors contributed equally to this work.
Abstract
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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.290619.116.
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Freely available online through the Genes & Development Open Access option.
- Received December 10, 2015.
- Accepted September 29, 2016.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.