The Pluripotency Factor NANOG Binds to GLI Proteins and Represses Hedgehog-mediated Transcription

J Biol Chem. 2016 Mar 25;291(13):7171-82. doi: 10.1074/jbc.M116.714857. Epub 2016 Jan 21.


The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We found that both GLI3 and GLI1 bind to the pluripotency factor NANOG. The ectopic expression of NANOG inhibits GLI1-mediated transcriptional responses in a dose-dependent fashion. In differentiating ES cells, the presence of NANOG reduces the transcriptional response of cells to HH. Finally, we found thatGli1andNanogare co-expressed in ES cells at high levels. We propose that NANOG acts as a negative feedback component that provides stem cell-specific regulation of the HH pathway.

Keywords: GLI proteins; Hedgehog signaling pathway; Nanog; differentiation; embryonic stem cell; repressor; stem cells; transcription repressor.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Feedback, Physiological
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • NIH 3T3 Cells
  • Nanog Homeobox Protein
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Protein Binding
  • Signal Transduction
  • Transcription, Genetic
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli3


  • Gli1 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Nerve Tissue Proteins
  • Shh protein, mouse
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli3