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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 a...

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Autores principales: Kellogg, Ryan A, Tian, Chengzhe, Lipniacki, Tomasz, Quake, Stephen R, Tay, Savaş
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608393/
https://www.ncbi.nlm.nih.gov/pubmed/26488364
http://dx.doi.org/10.7554/eLife.08931
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author Kellogg, Ryan A
Tian, Chengzhe
Lipniacki, Tomasz
Quake, Stephen R
Tay, Savaş
author_facet Kellogg, Ryan A
Tian, Chengzhe
Lipniacki, Tomasz
Quake, Stephen R
Tay, Savaş
author_sort Kellogg, Ryan A
collection PubMed
description 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. DOI: http://dx.doi.org/10.7554/eLife.08931.001
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spelling pubmed-46083932015-10-22 Digital signaling decouples activation probability and population heterogeneity Kellogg, Ryan A Tian, Chengzhe Lipniacki, Tomasz Quake, Stephen R Tay, Savaş eLife Computational and Systems Biology 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. DOI: http://dx.doi.org/10.7554/eLife.08931.001 eLife Sciences Publications, Ltd 2015-10-21 /pmc/articles/PMC4608393/ /pubmed/26488364 http://dx.doi.org/10.7554/eLife.08931 Text en © 2015, Kellogg et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Kellogg, Ryan A
Tian, Chengzhe
Lipniacki, Tomasz
Quake, Stephen R
Tay, Savaş
Digital signaling decouples activation probability and population heterogeneity
title Digital signaling decouples activation probability and population heterogeneity
title_full Digital signaling decouples activation probability and population heterogeneity
title_fullStr Digital signaling decouples activation probability and population heterogeneity
title_full_unstemmed Digital signaling decouples activation probability and population heterogeneity
title_short Digital signaling decouples activation probability and population heterogeneity
title_sort digital signaling decouples activation probability and population heterogeneity
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608393/
https://www.ncbi.nlm.nih.gov/pubmed/26488364
http://dx.doi.org/10.7554/eLife.08931
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