Resetting Transcription Factor Control Circuitry Toward Ground-State Pluripotency in Human

Cell. 2014 Sep 11;158(6):1254-1269. doi: 10.1016/j.cell.2014.08.029.

Abstract

Current human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here, we report that short-term expression of two components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signaling, are phenotypically stable, and are karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground-state transcription factors, TFCP2L1 or KLF4, has marginal impact on conventional human pluripotent stem cells but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytological Techniques
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Epigenesis, Genetic
  • Homeodomain Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Nanog Homeobox Protein
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • Homeodomain Proteins
  • KLF2 protein, human
  • Kruppel-Like Transcription Factors
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Transcription Factors

Associated data

  • GEO/GSE60945