Digital signaling decouples activation probability and population heterogeneity
Digital signaling decouples activation probability and population heterogeneity
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DOI：
10.7554/elife.08931
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发表时间：
2015-10-21
期刊：
影响因子：
7.7
通讯作者：
Tay, Savas
中科院分区：
文献类型：
--
作者：
Kellogg, Ryan A.;Tian, Chengzhe;Tay, Savas
数字信号增强了在嘈杂环境中细胞决策的鲁棒性，但目前还不清楚数字系统如何传输有关刺激的时间信息。为了了解NF-κ B B系统是如何编码和解码时间输入信息的，我们研究了剂量和持续时间调节的炎症输入下的转录因子动力学和基因调控。数学建模预测和微流体单细胞实验证实，刺激的积分（或面积，浓度x持续时间）控制了群体中激活NF-κ B的细胞的分数。然而，刺激时间曲线决定NF-κ B动力学、细胞间变异性和基因表达表型。持续的弱刺激导致异质性激活和传递到基因表达的延迟时间。与此相反，一个短暂的，强烈的刺激与相同的区域引起快速和均匀的动态。这些结果表明，数字NF-κ B信号传导能够通过输入谱多维控制细胞表型，允许平行和独立控制单细胞活化概率和群体异质性。
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-kappa B 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 x duration) controls the fraction of cells that activate NF-kappa B in the population. However, stimulus temporal profile determined NF-kappa B 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-kappa B signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity.