STAT3 and Oct-3/4 control histone modification through induction of Eed in embryonic stem cells

J Biol Chem. 2008 Apr 11;283(15):9713-23. doi: 10.1074/jbc.M707275200. Epub 2008 Jan 16.


Mouse embryonic stem (ES) cells can self-renew in the presence of leukemia inhibitory factor (LIF). Several essential transcription factors have been identified for the self-renewal of mouse ES cells, including STAT3, Oct-3/4, and Nanog. The molecular mechanism of ES cell self-renewal, however, is not fully understood. In the present study, we identified Eed, a core component of Polycomb repressive complex 2, as a downstream molecule of STAT3 and Oct-3/4. Artificial activation of STAT3 resulted in increased expression of Eed, whereas expression of a dominant negative mutant of STAT3 or suppression of Oct-3/4 expression led to down-regulation of Eed. Reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that STAT3 and Oct-3/4 directly bind to the promoter region of Eed, suggesting that Eed is a common target molecule of STAT3 and Oct-3/4. We also found that suppression of STAT3, Oct-3/4, or Eed causes induction of differentiation-associated genes as well as loss of Lys(27)-trimethylated histone H3 at the promoter regions of the differentiation-associated genes. Suppression of STAT3 and Oct-3/4 also resulted in the absence of Eed at the promoter regions. These results suggest that STAT3 and Oct-3/4 maintain silencing of differentiation-associated genes through up-regulation of Eed in self-renewing ES cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Line
  • Cell Proliferation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Gene Silencing / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia Inhibitory Factor / pharmacology
  • Mice
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism*
  • Polycomb Repressive Complex 2
  • Promoter Regions, Genetic / physiology*
  • Protein Binding / physiology
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*


  • DNA-Binding Proteins
  • Eed protein, mouse
  • Homeodomain Proteins
  • LIF protein, human
  • Leukemia Inhibitory Factor
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Polycomb Repressive Complex 2