Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells

• Published in: Stem cell reports 2015-07, Vol.5 (1), p.10-21
• Main Authors: Wu, Liangtang, Wary, Kishore K., Revskoy, Sergei, Gao, Xiaopei, Tsang, Kitman, Komarova, Yulia A., Rehman, Jalees, Malik, Asrar B.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Cadherins - genetics; Cadherins - metabolism; Cell Differentiation - genetics; Embryonic Stem Cells - metabolism; Endothelial Cells - metabolism; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Histone Demethylases - genetics; Histones - genetics; Histones - metabolism; Jumonji Domain-Containing Histone Demethylases - genetics; Mice; Promoter Regions, Genetic; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Zebrafish
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2015.05.016

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. •Histone demethylases KDM4A and KDM4C are upregulated in endothelial differentiation•KDM4A and KDM4A bind to histones associated with Flk1 and VE-cadherin promoters•Depletion of either KDM4A or KDM4C in mESCs prevented endothelial differentiation•Depletion of KDM4A and KDM4C prevented blood vessel formation in zebrafish In this article, Malik, Rehman, and colleagues show that the histone demethylases KDM4A and KDM4C are upregulated during the differentiation of mouse embryonic stem cells into vascular endothelial cells. Depletion of these two histone demethylases suppressed endothelial differentiation and angiogenesis in vitro as well as vascular development in a zebrafish model.