Partner: Timothy Lee

Stanford University (US)

Ostatnie publikacje
1.Tay S., Hughey J.J., Lee T.K., Lipniacki T., Quake S.R., Covert M.W., Single-cell NF-kB dynamics reveal digital activation and analogue information processing, NATURE, ISSN: 0028-0836, DOI: 10.1038/nature09145, Vol.466, pp.267-271, 2010


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 types1. 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 intensities2. Here we use high-throughput microfluidic cell culture3 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 assays2, 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.

Słowa kluczowe:

Cell biology, Biophysics, Immunology, Genetics, Genomics

Afiliacje autorów:

Tay S.-Eidgenössische Technische Hochschule Zürich (CH)
Hughey J.J.-Stanford University (US)
Lee T.K.-Stanford University (US)
Lipniacki T.-IPPT PAN
Quake S.R.-Stanford University (US)
Covert M.W.-Stanford University (US)