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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / embryology*
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA Primers / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenetic Repression / genetics
  • Epigenetic Repression / physiology*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation, Developmental / physiology*
  • In Situ Hybridization
  • Kruppel-Like Transcription Factors
  • Luciferases
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Microscopy, Electron, Transmission
  • Nerve Tissue Proteins / metabolism
  • Organic Chemicals
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • Signal Transduction / physiology*

Substances

  • Creb3l1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • DNA Primers
  • Klf5 protein, mouse
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Organic Chemicals
  • Proto-Oncogene Proteins c-fos
  • fos-related antigen 1
  • SYBR Green I
  • Luciferases
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse