E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1.
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.
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Bart G M W
BG
Weijts
Walbert J
WJ
Bakker
Peter W A
PW
Cornelissen
Kuo-Hsuan
KH
Liang
Frank H
FH
Schaftenaar
Bart
B
Westendorp
Charlotte A C M T
CA
de Wolf
Maya
M
Paciejewska
Colinda L G J
CL
Scheele
Lindsey
L
Kent
Gustavo
G
Leone
Stefan
S
Schulte-Merker
Alain
A
de Bruin
D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D015027:Zebrafish
D050684:E2F Transcription Factors; D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A