Digital signaling decouples activation probability and population heterogeneity.
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.
Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland.
Ryan A
http://orcid.org/0000-0002-5591-9466
RA
Kellogg
Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
Chengzhe
http://orcid.org/0000-0002-2269-1979
C
Tian
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Tomasz
T
Lipniacki
Department of Bioengineering, Howard Hughes Medical Institute, Stanford University, Stanford, United States.
Stephen R
SR
Quake
Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule Zürich, Basel, Switzerland.|Institute for Molecular Engineering, University of Chicago, Chicago, United States.
Savaş
S
Tay
D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D044085:Microfluidics; D008962:Models, Theoretical; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D013997:Time Factors
D016328:NF-kappa B
cell-to-cell heterogeneity; computational biology; digital signaling; immunology; innate immunity; mouse; signaling dynamics; single-cell analysis; systems biology