ERRs mediate a metabolic switch required for somatic cell reprogramming to pluripotency

Yasuyuki S. Kida, Teruhisa Kawamura, Zong Wei, Takahiro Sogo, Sandra Jacinto, Asako Shigeno, Hiroko Kushige, Eiji Yoshihara, Christopher Liddle, Joseph R. Ecker, Ruth T. Yu, Annette R. Atkins, Michael Downes, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Cell metabolism is adaptive to extrinsic demands; however, the intrinsic metabolic demands that drive the induced pluripotent stem cell (iPSC) program remain unclear. Although glycolysis increases throughout the reprogramming process, we show that the estrogen-related nuclear receptors (ERRα and ERRγ) and their partnered co-factors PGC-1α and PGC-1β are transiently induced at an early stage, resulting in a burst of oxidative phosphorylation (OXPHOS) activity. Upregulation of ERRα or ERRγ is required for the OXPHOS burst in both human and mouse cells, respectively, as well as iPSC generation itself. Failure to induce this metabolic switch collapses the reprogramming process. Furthermore, we identify a rare pool of Sca1-/CD34- sortable cells that is highly enriched in bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors are ERRγ and PGC-1β positive and have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic gate prior to establishment of induced pluripotency.

Original languageEnglish (US)
Pages (from-to)547-555
Number of pages9
JournalCell Stem Cell
Volume16
Issue number5
DOIs
StatePublished - May 7 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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