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

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

Author information

1
Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: suzanne_gaudet@dfci.harvard.edu.

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.

PMID:
24530305
PMCID:
PMC3977799
DOI:
10.1016/j.molcel.2014.01.026
[Indexed for MEDLINE]
Free PMC Article

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