Digital signaling decouples activation probability and population heterogeneity

• Main Authors: Ryan A Kellogg, Chengzhe Tian, Tomasz Lipniacki, Stephen R Quake, Savaş Tay
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2015-10-01
• Series: eLife
• Subjects: digital signaling; single-cell analysis; signaling dynamics; cell-to-cell heterogeneity; systems biology; innate immunity
• Online Access: https://elifesciences.org/articles/08931

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.