Fold change of nuclear NF-κB determines TNF-induced transcription in single cells.

Academic Article


  • In response to tumor necrosis factor (TNF), NF-κB enters the nucleus and promotes inflammatory and stress-responsive gene transcription. Because NF-κB deregulation is associated with disease, one might expect strict control of NF-κB localization. However, nuclear NF-κB levels exhibit considerable cell-to-cell variability, even in unstimulated cells. To resolve this paradox and determine how transcription-inducing signals are encoded, we quantified single-cell NF-κB translocation dynamics and transcription in the same cells. We show that TNF-induced transcription correlates best with fold change in nuclear NF-κB, not absolute nuclear NF-κB abundance. Using computational modeling, we find that an incoherent feedforward loop, from competition for binding to κB motifs, could provide memory of the preligand state necessary for fold-change detection. Experimentally, we observed three gene-specific transcriptional patterns that our model recapitulates by modulating competition strength alone. Fold-change detection buffers against stochastic variation in signaling molecules and explains how cells tolerate variability in NF-κB abundance and localization.
  • Authors

  • Lee, Robin EC
  • Walker, Sarah
  • Savery, Kate
  • Frank, David A
  • Gaudet, Suzanne
  • Status

    Publication Date

  • March 20, 2014
  • Published In

  • Molecular Cell  Journal
  • Keywords

  • Binding Sites
  • Binding, Competitive
  • Cell Nucleus
  • Computer Simulation
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Ligands
  • Models, Statistical
  • Molecular Imaging
  • NF-kappa B
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • RNA, Messenger
  • Signal Transduction
  • Single-Cell Analysis
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha
  • Digital Object Identifier (doi)

    Start Page

  • 867
  • End Page

  • 879
  • Volume

  • 53
  • Issue

  • 6