Controlling low rates of cell differentiation through noise and ultrahigh feedback

Science. 2014 Jun 20;344(6190):1384-9. doi: 10.1126/science.1252079.


Mammalian tissue size is maintained by slow replacement of de-differentiating and dying cells. For adipocytes, key regulators of glucose and lipid metabolism, the renewal rate is only 10% per year. We used computational modeling, quantitative mass spectrometry, and single-cell microscopy to show that cell-to-cell variability, or noise, in protein abundance acts within a network of more than six positive feedbacks to permit pre-adipocytes to differentiate at very low rates. This reconciles two fundamental opposing requirements: High cell-to-cell signal variability is needed to generate very low differentiation rates, whereas low signal variability is needed to prevent differentiated cells from de-differentiating. Higher eukaryotes can thus control low rates of near irreversible cell fate decisions through a balancing act between noise and ultrahigh feedback connectivity.

Publication types

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

MeSH terms

  • Adipocytes / cytology*
  • Adipogenesis*
  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Communication
  • Cell Differentiation
  • Cell Line
  • Computer Simulation
  • Feedback, Physiological
  • Mass Spectrometry
  • Mice
  • Models, Biological*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • RNA, Small Interfering / genetics
  • Single-Cell Analysis
  • Stem Cells / cytology


  • CCAAT-Enhancer-Binding Proteins
  • PPAR gamma
  • RNA, Small Interfering