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Nat Commun March 6, 2019; 10 (1): 1083.
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Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos.

Li L , Rispoli R , Patient R , Ciau-Uitz A , Porcher C .

VEGFA signaling controls physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VEGFA have been uncovered, vegfa transcriptional regulation in vivo remains unclear. Here, we show that the ETS transcription factor, Etv6, positively regulates vegfa expression during Xenopus blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of the repressor foxo3, to prevent Foxo3 from binding to and repressing the vegfa promoter. Etv6 also directly activates expression of the activator klf4; reflecting a genome-wide paucity in ETS-binding motifs in Etv6 genomic targets, Klf4 then recruits Etv6 to the vegfa promoter to activate its expression. These two mechanisms (double negative gate and feed-forward loop) are classic features of gene regulatory networks specifying cell fates. Thus, Etv6''s dual function, as a transcriptional repressor and activator, controls a major signaling pathway involved in endothelial and blood development in vivo.

PubMed ID: 30842454
PMC ID: PMC6403364
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: crim1 etv6 foxo3 grn klf4 ldb1 lmo2 meox2 mmut odc1 runx1 sox18 tal1 vegfa
GO keywords: angiogenesis [+]
Morpholinos: etv6 MO1 foxo3 MO2 foxo3 MO3 klf4 MO4

GEO Series: GSE115220: NCBI
GSE115224: NCBI
GSE115225: NCBI

Article Images: [+] show captions
References [+] :
Aiello, Echoes of the embryo: using the developmental biology toolkit to study cancer. 2016, Pubmed