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Elife. 2015 Oct 21;4:e08931. doi: 10.7554/eLife.08931.

Digital signaling decouples activation probability and population heterogeneity.

Author information

1
Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland.
2
Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
3
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
4
Department of Bioengineering, Howard Hughes Medical Institute, Stanford University, Stanford, United States.
5
Institute for Molecular Engineering, University of Chicago, Chicago, United States.

Abstract

Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-κB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration × duration) controls the fraction of cells that activate NF-κB in the population. However, stimulus temporal profile determined NF-κB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-κB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity.

KEYWORDS:

cell-to-cell heterogeneity; computational biology; digital signaling; immunology; innate immunity; mouse; signaling dynamics; single-cell analysis; systems biology

PMID:
26488364
PMCID:
PMC4608393
DOI:
10.7554/eLife.08931
[Indexed for MEDLINE]
Free PMC Article

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