EZH2 regulates neuronal differentiation of mesenchymal stem cells through PIP5K1C-dependent calcium signaling

J Biol Chem. 2011 Mar 18;286(11):9657-67. doi: 10.1074/jbc.M110.185124. Epub 2011 Jan 7.


Enhancer of zeste homolog 2 (EZH2) regulates stem cells renewal, maintenance, and differentiation into different cell lineages including neuron. Changes in intracellular Ca(2+) concentration play a critical role in the differentiation of neurons. However, whether EZH2 modulates intracellular Ca(2+) signaling in regulating neuronal differentiation from human mesenchymal stem cells (hMSCs) still remains unclear. When hMSCs were treated with a Ca(2+) chelator or a PLC inhibitor to block IP(3)-mediated Ca(2+) signaling, neuronal differentiation was disrupted. EZH2 bound to the promoter region of PIP5K1C to suppress its transcription in proliferating hMSCs. Interestingly, knockdown of EZH2 enhanced the expression of PIP5K1C, which in turn increased the amount of PI(4,5)P(2), a precursor of IP(3), and resulted in increasing the intracellular Ca(2+) level, suggesting that EZH2 negatively regulates intracellular Ca(2+) through suppression of PIP5K1C. Knockdown of EZH2 also enhanced hMSCs differentiation into functional neuron both in vitro and in vivo. In contrast, knockdown of PIP5K1C significantly reduced PI(4,5)P(2) contents and intracellular Ca(2+) release in EZH2-silenced cells and resulted in the disruption of neuronal differentiation from hMSCs. Here, we provide the first evidence to demonstrate that after induction to neuronal differentiation, decreased EZH2 activates the expression of PIP5K1C to evoke intracellular Ca(2+) signaling, which leads hMSCs to differentiate into functional neuron lineage. Activation of intracellular Ca(2+) signaling by repressing or knocking down EZH2 might be a potential strategy to promote neuronal differentiation from hMSCs for application to neurological dysfunction diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Gene Knockdown Techniques
  • Humans
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Nervous System Diseases / genetics
  • Nervous System Diseases / metabolism
  • Nervous System Diseases / therapy
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / biosynthesis*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Polycomb Repressive Complex 2
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Chelating Agents
  • DNA-Binding Proteins
  • Transcription Factors
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Calcium