Details

Autor(en) / Beteiligte

• Lee, Robin E.C.
• Walker, Sarah R.
• Savery, Kate
• Frank, David A.
• Gaudet, Suzanne

Titel

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

Ist Teil von

• Molecular cell, 2014-03, Vol.53 (6), p.867-879

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Transcript numbers for NF-κB-dependent genes vary less than nuclear NF-κB abundance•Fold change of nuclear NF-κB is a quantitative predictor of transcript number•Individual target genes interpret fold change signals distinctly•An I1-FFL model recapitulates patterns of transcription and fold-change detection In the nucleus, NF-κB family protein RelA coordinates inflammatory and survival gene expression, yet its nuclear abundance varies substantially from cell to cell. Using single-cell correlations, Lee et al. show that RelA transcription-inducing signals are encoded by fold change in nuclear RelA, buffering against variation in its prestimulus nuclear abundance.