Bilateral NSF/BIO-BBSRC: Signal encoding by transcription factor pulsing and its functional advantages

细胞信号是许多生物过程的基础，从胚胎的发育到癌细胞的生长。信号系统是由一组基因及其表达产物蛋白质组成的，它们通过控制相应基因的表达而相互作用。转录因子是调节信号系统中一组基因表达的蛋白质，通过与靶基因上游的特定DNA序列基序结合来实现。通过用传统的生物化学方法测量细胞群中转录因子的数量，生物学家已经证明，环境输入（即压力或细胞外配体）可以改变调节基因表达的转录因子的浓度。该项目的目的是了解单个细胞如何将外部输入编码为基于时间的信号，以及这些信号如何传递给下游基因，并检查单个细胞的行为与细胞群体的行为有何不同。来自加州理工学院（美国）和爱丁堡大学（英国）的合作研究小组将使用基于荧光蛋白和延时光学显微镜技术的新的单细胞测量方法，可以提供关于单个细胞信号处理能力的新的和独特的信息。通过其更广泛的影响，该项目将促进对细胞信息处理动态性质的理解。此外，该项目将提供新的技术和工具来干扰和控制细胞的功能。细胞信号是许多生物过程的基础，从胚胎发育到疾病进展。它通常被认为是一个连续的、以浓度为基础的过程，其中细胞外输入以一种或多种转录因子（tf）或其他调节因子的浓度编码，这些转录因子又被解码以连续的方式控制基因表达。相比之下，最近的单细胞研究表明，许多中枢tf在响应输入的随机脉冲中被激活。例子包括哺乳动物中的核因子κ b和p53，以及酵母中的一般应激调节因子Msn2。在这些系统中，输入产生TF活性脉冲，然后由目标启动子以动态方式解码。脉冲系统中信号编码和解码的程度以及这些系统潜在的生理功能在很大程度上仍未被探索。该项目将通过Swain和Elowitz实验室之间的合作努力来解决这些问题。该团队将整合单细胞延时显微镜、微流体和信息论技术，通过研究单细胞中TF动态的编码和解码，来测量动态信号系统中的信息传递。该项目将有助于了解动态信号的三个方面：首先，该团队将生成应力和TF动态之间输入-输出关系的广泛数据集，提供对动态细胞反应的全面理解。其次，单细胞信号的信息理论分析将为基于动态的信息转导和基于脉冲的信号编码和解码提供更全面的视角。第三，探索动态脉冲的生理作用，开辟通过扰动TF动力学来控制细胞行为的可能性。通过其更广泛的影响，这种对细胞中基于脉冲的信号的分析应该使科学家能够理解自然信号系统的设计原则。这个英美合作项目由美国国家科学基金会和英国生物技术和生物科学研究委员会支持。

Cellular signaling is fundamental to many biological processes, from the development of embryos to the growth of cancerous cells. Signaling systems are composed of a cluster of genes and their expression products, proteins, which can interact with each other by controlling the expression of the corresponding gene. Transcription factors are proteins that regulate the expression of a group of genes within signaling systems and do so by binding to a specific DNA sequence motif upstream of targeting genes. By measuring the amount of transcription factors from a population of cells with traditional biochemistry assays, biologists have shown that environmental inputs (i.e., stresses or extracellular ligands) can alter the concentrations of transcription factors that regulate gene expression. The objective of this project is to understand how individual cells encode external inputs as time-based signals and how these signals are transmitted to downstream genes, and to examine how the single cell behavior differs from the behavior of the population of cells. The collaborative team of investigators from the California Institute of Technology (US) and the University of Edinburgh (UK) will use new single-cell measurements based on fluorescent protein and time-lapse optical microscopy techniques can provide new and distinct information about the signal processing capabilities of individual cells. Through its broader impacts, this project will promote understanding of the dynamic nature of cellular information processing. Furthermore, this project will provide new techniques and tools to perturb and control cell functions.Cellular signaling is fundamental to many biological processes, from embryo development to disease progression. It is often considered to be a continuous and concentration-based process, where extracellular input is encoded in the concentrations of one or more transcription factors (TFs) or other regulators, which are in turn decoded to control gene expression in a continuous fashion. In contrast, recent single-cell studies have revealed that many central TFs are activated in stochastic pulses in response to inputs. Examples include nuclear factor-kappa-B and p53 in mammals, and the general stress regulator Msn2 in yeast. In these systems, inputs generate pulses of TF activity, which are then decoded by target promoters in a dynamic fashion. The extent of signal encoding and decoding in pulsing systems as well as the potential physiological functions of these systems remain largely unexplored. This project will address these questions in budding yeast through collaborative efforts between the Swain and the Elowitz laboratories. The team will integrate single-cell time-lapse microscopy, microfluidics, and techniques from information theory to measure the information transfer within dynamic signaling systems by investigating the encoding and decoding of TF dynamics in single cells. This project will contribute to the understanding of three aspects of dynamic signaling: First, the team will produce an extensive dataset of input- output relationship between stresses and TF dynamics, providing a comprehensive understanding of dynamic cellular responses. Second, information theoretical analysis of single-cell signaling will provide a more comprehensive view of dynamics-based information transduction and pulse-based signal encoding and decoding. Third, it will explore the physiological roles of dynamic pulsing, to open up the possibility of controlling cellular behaviors through the perturbation of TF dynamics. Through its broader impacts, this analysis of pulse-based signaling in cells should allow scientists to understand the design principles of natural signaling systems.This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.