title: Fold change of nuclear NF-κB determines TNF-induced transcription in single cells.
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.
authors: 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.
authors: Robin E C
authors: RE
authors: Lee
authors: 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.
authors: Sarah R
authors: SR
authors: Walker
authors: Department of Cancer Biology and Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Kate
authors: K
authors: Savery
authors: 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.
authors: David A
authors: DA
authors: Frank
authors: 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.
authors: Suzanne
authors: S
authors: Gaudet
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D003198:Computer Simulation; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D015233:Models, Statistical; D057054:Molecular Imaging; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha