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ZFIN ID: ZDB-PUB-150630-4
Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells
Wu, L., Wary, K.K., Revskoy, S., Gao, X., Tsang, K., Komarova, Y.A., Rehman, J., Malik, A.B.
Date: 2015
Source: Stem Cell Reports   5(1): 10-21 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • 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
PubMed: 26120059 Full text @ Stem Cell Reports
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.