Single-cell NF-κB dynamics reveal digital activation and analog information processing in cells
By S. Tay, J. Hughey, Timothy K. Lee, T. Lipniacki, Stephen R. Quake, Markus W. Covert. Nature, 2010
747 citations recorded by the source corpus.
Cells operate in dynamic environments using extraordinary communication capabilities that emerge from the interactions of genetic circuitry. The mammalian immune response is a striking example of the coordination of different cell types. Cell-to-cell communication is primarily mediated by signalling molecules that form spatiotemporal concentration gradients, requiring cells to respond to a wide range of signal intensities. Here we use high-throughput microfluidic cell culture and fluorescence microscopy, quantitative gene expression analysis and mathematical modelling to investigate how single mammalian cells respond to different concentrations of the signalling molecule tumour-necrosis factor (TNF)-α, and relay information to the gene expression programs by means of the transcription factor nuclear factor (NF)-κB. We measured NF-κB activity in thousands of live cells under TNF-α doses covering four orders of magnitude. We find, in contrast to population-level studies with bulk assays, that the activation is heterogeneous and is a digital process at the single-cell level with fewer cells responding at lower doses. Cells also encode a subtle set of analogue parameters to modulate the outcome; these parameters include NF-κB peak intensity, response time and number of oscillations. We developed a stochastic mathematical model that reproduces both the digital and analogue dynamics as well as most gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α-induced NF-κB signalling in various types of cells. These results highlight the value of high-throughput quantitative measurements with single-cell resolution in understanding how biological systems operate.
Subfields: Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/c9d99a6f42acf0eda685e319f00e6f1ec8d418e5
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In Immunology
In Molecular Biology
- Aviv Regev
- Rahul Satija
- Nir Yosef
- Nir Friedman
- Jeremy E. Purvis
- Nir Hacohen
- A. Shalek
- Schraga Schwartz
Citations in the corpus
- NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration (2019, background): “Put simply, a cell either responds to the cytokine or not, with increasing dose leading to more cells being activated, accompanied by single-cell level increases in activation strength at higher concentrations of TNF (37, 42).”
- Single cell RNA Seq reveals dynamic paracrine control of cellular variation (2014, methodology): “For each pair of consecutive time points, we examined the proportion of genes in each module with a significant change in: (1)m (Wilcoxon rank-sum test); (2)a (LRT, controlling for the aforementioned confounding relationship between average expression and detection efficiency, Supplementary Informat”
- Encoding and Decoding Cellular Information through Signaling Dynamics (2013, positive): “This negative feedback loop generates oscillations of transcriptionally active NFkB (Hoffmann et al., 2002; Nelson et al., 2004; Sung et al., 2009; Tay et al., 2010).”