Journal Article

Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos

Patient, Roger, Rispoli, Rossella, Porcher, Catherine, Li, Lei, Ciau-Uitz, Aldo

2019

Overview

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. How vegfa expression is transcriptionally regulated in vivo is unclear. Here, the authors demonstrate that the ETS transcription factor Etv6 acts as a repressor and an activator of two direct regulators of vegfa expression ( foxo3 and klf4 , respectively) to control blood formation in Xenopus .

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/71 / 38/91 / 49/15 / 631/136/334/1874/761 / 631/208 / 631/80 / 64/114 / 82/1 / 82/80 / Angiogenesis / Animals / Binding / Blood / Bone marrow / Cancer / Embryo, Nonmammalian / Embryos / Endothelium - embryology / Endothelium - metabolism / ETS protein / ETS Translocation Variant 6 Protein / Forkhead Box Protein O3 - antagonists & inhibitors / Forkhead Box Protein O3 - genetics / Forkhead Box Protein O3 - metabolism / FOXO3 protein / Gene expression / Gene Expression Regulation, Developmental - physiology / Gene regulation / Gene Regulatory Networks - physiology / Genes / Genomes / Hematopoiesis / Hematopoietic stem cells / Humanities and Social Sciences / KLF4 protein / Kruppel-Like Factor 4 / Kruppel-Like Transcription Factors - antagonists & inhibitors / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - metabolism / Morpholinos - genetics / multidisciplinary / Oligonucleotides, Antisense - genetics / Physiology / Polyclonal antibodies / Proteins / Proto-Oncogene Proteins c-ets - antagonists & inhibitors / Proto-Oncogene Proteins c-ets - genetics / Proto-Oncogene Proteins c-ets - metabolism / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Signal transduction / Signal Transduction - physiology / Signaling / Somites - embryology / Somites - metabolism / Stem cells / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism / Xenopus / Xenopus laevis - physiology / Xenopus Proteins - antagonists & inhibitors / Xenopus Proteins - genetics / Xenopus Proteins - metabolism