Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing.
Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing.
复制标题
单细胞 NF-kappaB 动力学揭示了数字激活和模拟信息处理。
作者：
细胞在不断变化的环境中运行，使用来自遗传电路相互作用的非凡通信能力。哺乳动物的免疫反应是不同细胞类型协调的一个突出例子。细胞与细胞之间的通讯主要由形成时空浓度梯度的信号分子介导，需要细胞对宽范围的信号强度做出反应。在这里，我们使用高通量微流控细胞培养，定量基因表达分析和数学建模来研究单个哺乳动物细胞如何响应于不同浓度的信号分子TNF-α，并通过转录因子NF-κB传递信息到基因表达程序。我们在四个数量级的TNF-α剂量下测量了数千个活细胞中的NF-κB活性。我们发现，与群体研究相反，激活是异质的，并且是单细胞水平的数字过程，在较低剂量下响应的细胞较少。细胞还编码一组微妙的模拟参数来调节结果;这些参数包括NF-κB峰强度、响应时间和振荡次数。我们开发了一个数学模型，再现了数字和模拟动力学以及在所有测量条件下的大多数基因表达谱，构成了TNF-α诱导的NF-κB信号转导在各种类型的细胞中的广泛适用的模型。这些结果突出了在单细胞水平上的高通量定量测量在理解生物系统如何运作方面的价值。
Cells operate in ever changing environments using extraordinary communication capabilities that emerge from the interactions of genetic circuitry. The mammalian immune response is a striking example of the coordination of different cell types. Cell-to-cell communication is primarily mediated by signaling molecules that form spatiotemporal concentration gradients, requiring cells to respond to a wide range of signal intensities. Here we use high-throughput microfluidic cell culture, quantitative gene expression analysis and mathematical modeling to investigate how single mammalian cells respond to different concentrations of the signaling molecule TNF-α, and relay information to the gene expression programs via the transcription factor NF-κB. We measured NF-κB activity in thousands of live cells under TNF-α doses covering four orders of magnitude. We find, in contrast to population studies, that the activation is heterogeneous and is a digital process at the single cell level with fewer cells responding at lower doses. Cells also encode a subtle set of analog parameters to modulate the outcome; these parameters include NF-κB peak intensity, response time and number of oscillations. We developed a mathematical model that reproduces both the digital and analog dynamics as well as the most gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α induced NF-κB signaling in various types of cells. These results highlight the value of high-throughput quantitative measurements at the single-cell level in understanding how biological systems operate.
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影响因子：
7.3
作者：
Lee, Timothy K.;Denny, Elissa M.;Covert, Markus W.
通讯作者：
Covert, Markus W.
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
DOI：
10.1073/pnas.0808831105
发表时间：
2008-12-30
影响因子：
11.1
作者：
St-Pierre, Francois;Endy, Drew
通讯作者：
Endy, Drew
影响因子：
30.8
作者：
Lahav, G;Rosenfeld, N;Alon, U
通讯作者：
Alon, U
影响因子：
56.9
作者：
Delhase, M;Hayakawa, M;Karin, M
通讯作者：
Karin, M