Fold Change of Nuclear NF-κB Determines TNF-induced Transcription in Single Cells

Mol Cell. 2014 Mar 20;53(6):867-79. doi: 10.1016/j.molcel.2014.01.026. Epub 2014 Feb 13.

Abstract

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.

Publication types

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

MeSH terms

  • Binding Sites
  • Binding, Competitive
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Computer Simulation
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Ligands
  • Models, Statistical*
  • Molecular Imaging
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Signal Transduction
  • Single-Cell Analysis
  • Transcription, Genetic*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Ligands
  • NF-kappa B
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha