title: Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1.
abstract: JmjC domain-containing proteins play a crucial role in the control of gene expression by acting as protein hydroxylases or demethylases, thereby controlling histone methylation or splicing. Here, we demonstrate that silencing of Jumonji domain-containing protein 6 (Jmjd6) impairs angiogenic functions of endothelial cells by changing the gene expression and modulating the splicing of the VEGF-receptor 1 (Flt1). Reduction of Jmjd6 expression altered splicing of Flt1 and increased the levels of the soluble form of Flt1, which binds to VEGF and placental growth factor (PlGF) and thereby inhibits angiogenesis. Saturating VEGF or PlGF or neutralizing antibodies directed against soluble Flt1 rescued the angiogenic defects induced by Jmjd6 silencing. Jmjd6 interacts with the splicing factors U2AF65 that binds to Flt1 mRNA. In conclusion, Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting.
authors.affiliation: Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Jes-Niels
authors.initials: JN
authors.lastname: Boeckel
authors.forename: Virginia
authors.initials: V
authors.lastname: Guarani
authors.forename: Masamichi
authors.initials: M
authors.lastname: Koyanagi
authors.forename: Tino
authors.initials: T
authors.lastname: Roexe
authors.forename: Andreas
authors.initials: A
authors.lastname: Lengeling
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Pascal
authors.initials: P
authors.lastname: Gellert
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D011499:Protein Processing, Post-Translational; D012326:RNA Splicing; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: C000608036:PGF protein, human; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C498707:JMJD6 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D040281:Vascular Endothelial Growth Factor Receptor-1