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

ABSTRACT: In response to tumor necrosis factor (TNF), NF-?B enters the nucleus and promotes inflammatory and stress-responsive gene transcription. Because NF-?B deregulation is associated with disease, one might expect strict control of NF-?B localization. However, nuclear NF-?B 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-?B translocation dynamics and transcription in the same cells. We show that TNF-induced transcription correlates best with fold change in nuclear NF-?B, not absolute nuclear NF-?B abundance. Using computational modeling, we find that an incoherent feedforward loop, from competition for binding to ?B 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-?B abundance and localization.

SUBMITTER: Lee RE 

PROVIDER: S-EPMC3977799 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature