Hybrid Cellular Metabolism Coordinated by Zic3 and Esrrb Synergistically Enhances Induction of Naive Pluripotency

Cell Metab. 2017 May 2;25(5):1103-1117.e6. doi: 10.1016/j.cmet.2017.04.017.


Naive pluripotent stem cells (PSCs) utilize both glycolysis and oxidative phosphorylation (OXPHOS) to satisfy their metabolic demands. However, it is unclear how somatic cells acquire this hybrid energy metabolism during reprogramming toward naive pluripotency. Here, we show that when transduced with Oct4, Sox2, and Klf4 (OSK) into murine fibroblasts, Zic3 and Esrrb synergistically enhance the reprogramming efficiency by regulating cellular metabolic pathways. These two transcription factors (TFs) cooperatively activate glycolytic metabolism independently of hypoxia inducible factors (HIFs). In contrast, the regulatory modes of the TFs on OXPHOS are antagonistic: Zic3 represses OXPHOS, whereas Esrrb activates it. Therefore, when introduced with Zic3, Esrrb restores OXPHOS activity, which is essential for efficient reprogramming. In addition, Esrrb-mediated OXPHOS activation is critical for the conversion of primed PSCs into the naive state. Our study suggests that the combinatorial function of TFs achieves an appropriate balance of metabolic pathways to induce naive PSCs.

Keywords: Esrrb; Mitochondria; Pgc1a; Zic3; epistem cell; hypoxia inducible factor.

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cellular Reprogramming*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Glycolysis*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Kruppel-Like Factor 4
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Oxidative Phosphorylation*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation


  • Esrrb protein, mouse
  • Homeodomain Proteins
  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Receptors, Estrogen
  • Transcription Factors
  • Zic3 protein, mouse