![]() Although the majority of biochemical information on cell signaling has been obtained from population level studies, it is not clear if population data faithfully reflect how individual cells respond. These results highlight the value of high-throughput quantitative measurements at the single-cell level in understanding how biological systems operate.Įukaryotic cells sense a wide range of signals via surface receptors and in turn mount specific responses by activating gene expression programs. We developed a mathematical model that reproduces both the digital and analog dynamics as well as the most gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α induced NF-κB signaling in various types of cells. Cells also encode a subtle set of analog parameters to modulate the outcome these parameters include NF-κB peak intensity, response time and number of oscillations. We find, in contrast to population studies, that the activation is heterogeneous and is a digital process at the single cell level with fewer cells responding at lower doses. ![]() We measured NF-κB activity in thousands of live cells under TNF-α doses covering four orders of magnitude. Here we use high-throughput microfluidic cell culture, quantitative gene expression analysis and mathematical modeling to investigate how single mammalian cells respond to different concentrations of the signaling molecule TNF-α, and relay information to the gene expression programs via the transcription factor NF-κB. 1 Cell-to-cell communication is primarily mediated by signaling molecules that form spatiotemporal concentration gradients, requiring cells to respond to a wide range of signal intensities. The mammalian immune response is a striking example of the coordination of different cell types. Cells operate in ever changing environments using extraordinary communication capabilities that emerge from the interactions of genetic circuitry.
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