title: Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells.
abstract: Understanding epigenetic mechanisms regulating embryonic stem cell (ESC) differentiation to endothelial cells may lead to increased efficiency of generation of vessel wall endothelial cells needed for vascular engineering. Here we demonstrated that the histone demethylases KDM4A and KDM4C played an indispensable but independent role in mediating the expression of fetal liver kinase (Flk)1 and VE-cadherin, respectively, and thereby the transition of mouse ESCs (mESCs) to endothelial cells. KDM4A was shown to bind to histones associated with the Flk1 promoter and KDM4C to bind to histones associated with the VE-cadherin promoter. KDM4A and KDM4C were also both required for capillary tube formation and vasculogenesis in mice. We observed in zebrafish that KDM4A depletion induced more severe vasculogenesis defects than KDM4C depletion, reflecting the early involvement of KDM4A in specifying endothelial cell fate. These findings together demonstrate the essential role of KDM4A and KDM4C in orchestrating mESC differentiation to endothelial cells through the activation of Flk1 and VE-cadherin promoters, respectively.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Liangtang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Wary
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Revskoy
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Kitman
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Komarova
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA; Section of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address: jalees@uic.edu.
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address: abmalik@uic.edu.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D056466:Histone Demethylases / Q000235:genetics*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D056466:Histone Demethylases; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C560307:JMJD2A protein, mouse; C544194:Jmjd2c protein, mouse