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Single-cell NF-κB dynamics reveal digital activation and analogue information processing

机译：单细胞NF-κB动力学揭示了数字激活和模拟信息处理

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摘要

Cells operate in dynamic 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 signalling 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 and fluorescence microscopy, quantitative gene expression analysis and mathematical modelling to investigate how single mammalian cells respond to different concentrations of the signalling molecule tumour-necrosis factor (TNF)-α, and relay information to the gene expression programs by means of the transcription factor nuclear 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-level studies with bulk assays, 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 analogue parameters to modulate the outcome; these parameters include NF-κB peak intensity, response time and number of oscillations. We developed a stochastic mathematical model that reproduces both the digital and analogue dynamics as well as most gene expression profiles at all measured conditions, constituting a broadly applicable model for TNF-α-induced NF-κB signalling in various types of cells. These results highlight the value of high-throughput quantitative measurements with single-cell resolution in understanding how biological systems operate.
机译：细胞利用遗传电路相互作用产生的非凡通信功能，在动态环境中运行。哺乳动物的免疫反应是不同细胞类型协调的突出例子。细胞之间的通讯主要是由形成时空浓度梯度的信号分子介导的，要求细胞对广泛的信号强度做出响应。在这里，我们使用高通量微流控细胞培养和荧光显微镜，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对不同浓度的信号分子肿瘤坏死因子（TNF）-α做出反应，并将信息传递给该基因转录因子核因子（NF）-κB表达程序。我们在覆盖四个数量级的TNF-α剂量下测量了数千个活细胞中的NF-κB活性。与通过大量测定进行的群体水平研究相反，我们发现激活是异质的，并且是单细胞水平的数字过程，较少的细胞在较低剂量下反应。细胞还编码一组细微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。我们开发了一种随机数学模型，可在所有测量条件下重现数字和模拟动态以及大多数基因表达谱，从而为各种类型的细胞中TNF-α诱导的NF-κB信号传导构建了广泛适用的模型。这些结果凸显了具有单细胞分辨率的高通量定量测量在理解生物系统如何运作方面的价值。

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  • 来源
    《Nature》 |2010年第7303期|P.267-271|共5页
  • 作者

    Savas Tay; rnJacob J. Hughey; rnTimothy K. Lee; rnTomasz Lipniacki; rnStephen R. Quake; rnMarkus W. Covert;

  • 作者单位

    Department of Bioengineering, Stanford University, Stanford, California 94305, USA Howard Hughes Medical Institute, Stanford, California 94305, USA;

    rnDepartment of Bioengineering, Stanford University, Stanford, California 94305, USA;

    rnDepartment of Bioengineering, Stanford University, Stanford, California 94305, USA;

    rnInstitute of Fundamental Technological Research, Warsaw 02-106, Poland;

    rnDepartment of Bioengineering, Stanford University, Stanford, California 94305, USA Howard Hughes Medical Institute, Stanford, California 94305, USA;

    rnDepartment of Bioengineering, Stanford University, Stanford, California 94305, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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