Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity

Ben D MacArthur, Ana Sevilla, Michael Lenz, Franz-Josef Müller, Berhard M Schuldt, Andreas A Schuppert, Sonya J Ridden, Patrick S Stumpf, Miguel Fidalgo, Avi Ma'ayan, Jianlong Wang, Ihor R Lemischka

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single-cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach that includes high-throughput single-cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced a more homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops have a role in controlling both ES cell fate decisions and population variability.

Original languageEnglish
Pages (from-to)1139-47
Number of pages9
JournalNature Cell Biology
Volume14
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • Animals
  • Cell Survival
  • Computational Biology
  • Embryonic Stem Cells
  • Flow Cytometry
  • Homeodomain Proteins
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Transcriptome

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