ZFIN ID: ZDB-PUB-120822-27
E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1
Weijts, B.G., Bakker, W.J., Cornelissen, P.W., Liang, K.H., Schaftenaar, F.H., Westendorp, B., de Wolf, C.A., Paciejewska, M., Scheele, C.L., Kent, L., Leone, G., Schulte-Merker, S., and de Bruin, A.
Date: 2012
Source: The EMBO journal   31(19): 3871-3884 (Journal)
Registered Authors: Schulte-Merker, Stefan
Keywords: angiogenesis, E2F, HIF, VEGF, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • E2F Transcription Factors/genetics
  • E2F Transcription Factors/metabolism*
  • Embryonic Development/genetics
  • Embryonic Development/physiology
  • Gene Deletion
  • Humans
  • Hypoxia-Inducible Factor 1/metabolism*
  • Mice
  • Neovascularization, Physiologic/genetics*
  • Promoter Regions, Genetic
  • Transcriptional Activation*
  • Vascular Endothelial Growth Factor A/genetics*
  • Zebrafish
PubMed: 22903062 Full text @ EMBO J.

The E2F family of transcription factors plays an important role in controlling cell-cycle progression. While this is their best-known function, we report here novel functions for the newest members of the E2F family, E2F7 and E2F8 (E2F7/8). We show that simultaneous deletion of E2F7/8 in zebrafish and mice leads to severe vascular defects during embryonic development. Using a panel of transgenic zebrafish with fluorescent-labelled blood vessels, we demonstrate that E2F7/8 are essential for proper formation of blood vessels. Despite their classification as transcriptional repressors, we provide evidence for a molecular mechanism through which E2F7/8 activate the transcription of the vascular endothelial growth factor A (VEGFA), a key factor in guiding angiogenesis. We show that E2F7/8 directly bind and stimulate the VEGFA promoter independent of canonical E2F binding elements. Instead, E2F7/8 form a transcriptional complex with the hypoxia inducible factor 1 (HIF1) to stimulate VEGFA promoter activity. These results uncover an unexpected link between E2F7/8 and the HIF1-VEGFA pathway providing a molecular mechanism by which E2F7/8 control angiogenesis.