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Development. 2014 Dec;141(23):4610-7. doi: 10.1242/dev.112607. Epub 2014 Oct 30.

Ezh2-mediated repression of a transcriptional pathway upstream of Mmp9 maintains integrity of the developing vasculature.

Author information

1
Gladstone Institute of Cardiovascular Disease, and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada Heart and Stroke Richard Lewar Centre of Excellence, Toronto, Ontario M5G 1L7, Canada paul.delgadoolguin@sickkids.ca bbruneau@gladstone.ucsf.edu.
2
Heart and Stroke Richard Lewar Centre of Excellence, Toronto, Ontario M5G 1L7, Canada Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A1, Canada.
3
Gladstone Institute of Cardiovascular Disease, and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
4
Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.
5
Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021, USA.
6
Gladstone Institute of Cardiovascular Disease, and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA Department of Pediatrics, Cardiovascular Research Institute, and Institute for Regeneration Medicine, University of California San Francisco, San Francisco, CA 94158, USA paul.delgadoolguin@sickkids.ca bbruneau@gladstone.ucsf.edu.

Abstract

Maintenance of vascular integrity is required for embryogenesis and organ homeostasis. However, the gene expression programs that stabilize blood vessels are poorly understood. Here, we show that the histone methyltransferase Ezh2 maintains integrity of the developing vasculature by repressing a transcriptional program that activates expression of Mmp9. Inactivation of Ezh2 in developing mouse endothelium caused embryonic lethality with compromised vascular integrity and increased extracellular matrix degradation. Genome-wide approaches showed that Ezh2 targets Mmp9 and its activators Fosl1 and Klf5. In addition, we uncovered Creb3l1 as an Ezh2 target that directly activates Mmp9 gene expression in the endothelium. Furthermore, genetic inactivation of Mmp9 rescued vascular integrity defects in Ezh2-deficient embryos. Thus, epigenetic repression of Creb3l1, Fosl1, Klf5 and Mmp9 by Ezh2 in endothelial cells maintains the integrity of the developing vasculature, potentially linking this transcriptional network to diseases with compromised vascular integrity.

KEYWORDS:

Endothelium; Epigenetics; Extracellular matrix; Ezh2; Histone methylation; Mmp9; Mouse; Vascular development; Vascular stability

PMID:
25359725
PMCID:
PMC4302930
DOI:
10.1242/dev.112607
[Indexed for MEDLINE]
Free PMC Article

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