title: An arterial-specific enhancer of the human endothelin converting enzyme 1 (ECE1) gene is synergistically activated by Sox17, FoxC2, and Etv2.
abstract: Endothelin-converting enzyme-1 (Ece-1), a crucial component of the Endothelin signaling pathway, is required for embryonic development and is an important regulator of vascular tone, yet the transcriptional regulation of the ECE1 gene has remained largely unknown. Here, we define the activity and regulation of an enhancer from the human ECE1 locus in vivo. The enhancer identified here becomes active in endothelial progenitor cells shortly after their initial specification and is dependent on a conserved FOX:ETS motif, a composite binding site for Forkhead transcription factors and the Ets transcription factor Etv2, for activity in vivo. The ECE1 FOX:ETS motif is bound and cooperatively activated by FoxC2 and Etv2, but unlike other described FOX:ETS-dependent enhancers, ECE1 enhancer activity becomes restricted to arterial endothelium and endocardium by embryonic day 9.5 in transgenic mouse embryos. The ECE1 endothelial enhancer also contains an evolutionarily-conserved, consensus SOX binding site, which is required for activity in transgenic mouse embryos. Importantly, the ECE1 SOX site is bound and activated by Sox17, a transcription factor involved in endothelial cell differentiation and an important regulator of arterial identity. Moreover, the ECE1 enhancer is cooperatively activated by the combinatorial action of FoxC2, Etv2, and Sox17. Although Sox17 is required for arterial identity, few direct transcriptional targets have been identified in endothelial cells. Thus, this work has important implications for our understanding of endothelial specification and arterial subspecification.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Robinson
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Materna
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517.
authors.forename: Ralston M
authors.initials: RM
authors.lastname: Barnes
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517.
authors.forename: Sarah
authors.initials: S
authors.lastname: De Val
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517.
authors.forename: Shan-Mei
authors.initials: SM
authors.lastname: Xu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517.|Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004699:Endocardium / Q000196:embryology* / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000196:embryology* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005697:Galactosides; D006801:Humans; D007211:Indoles; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D055747:SOX Transcription Factors / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C503994:ER71 protein, mouse; D051858:Forkhead Transcription Factors; D005697:Galactosides; D007211:Indoles; D055747:SOX Transcription Factors; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
keywords: Artery; Ece-1; Embryo; Endothelin; Etv2; FoxC2; Mouse; Sox17; Vasculogenesis; Vein