Feedback regulation and transcirptional coupling in bacterial stress-response

描述(由申请人提供)：活细胞的一个关键属性是它们通过特定的生化反应对内部或外部刺激做出反应的能力。通过基因表达的变化，细菌已经进化出对环境刺激的感知和快速适应。调节这些反应的应激反应网络的分子细节已经在许多模式细菌中被发现。然而，我们仍然缺乏跨物种的这些反应的网络层面的知识，这对于更深入地了解细胞功能和最好地将模型细菌获得的结果应用于特征不佳或不能在实验室培养的致病细菌物种是必要的。在本应用中，我们将重点放在细菌应激反应网络的两个常见的基本构件上：双组分系统和交替的西格玛因子网络。结合理论、计算和实验方法，我们的多学科团队将探索网络组织的两个重要方面-由于转录自动调节和同一操纵子中网络基因的共转录而产生的反馈环。具体目的是(SA1)了解来自单个操纵子的细菌基因的共同表达与相应网络信息处理中的随机性之间的关系，以及(SA2)评估反馈调节在替代西格玛因子和两组分系统网络中的作用。对于每个特定的目标，研究计划将包括三个基本组成部分：(1)建立和分析具有生物物理真实性但易于分析的应激反应网络主调节模块模型，(2)模拟和分析模型有机体污垢分枝杆菌中特定网络的详细模型，以及(3)对污垢分枝杆菌的预测进行实验测试。这将导致理论/模型和实验之间的迭代和协同反馈。这项拟议工作的结果有望揭示新的进化设计原则，这些原则表征了跨细菌物种的网络结构和动态性能之间的关系，这对于操纵自然发生的网络和设计合成基因电路是必不可少的。

DESCRIPTION (provided by applicant): A key property of living cells is their ability to react to internal or external stimuli with specific biochemical responses. Bacteria have evolved to sense and rapidly adapt to environmental stimuli by changes in gene expression. Molecular details of the stress response networks regulating these responses have been uncovered for many model bacteria. However, we still lack network-level knowledge of these responses across species, which is necessary to obtain a deeper understanding of cellular functions and to best apply results obtained with model bacteria to pathogenic bacterial species that are poorly characterized or cannot be cultured in a laboratory. In this application we focus on two of the common basic building blocks of bacterial stress-response networks: two-component systems and alternative sigma-factor networks. Combining theoretical, computational and experimental approaches, our multi-disciplinary team will explore two important aspects of network organization - feedback loops due to transcriptional autoregulation and co-transcription of network genes in the same operon. The Specific Aims are (SA1) To understand the relationship between co-expression of bacterial genes from a single operon and stochasticity in information processing of the corresponding networks and (SA2) To assess the role of feedback regulation in alternative sigma factor and two-component system networks. For each Specific Aim the research plan will involve three essential components: (1) formulation and analysis of biophysically realistic but analytically tractable models of master-regulation modules of stress-response networks, (2) simulations and analysis of detailed models of particular networks in the model organism Mycobacterium smegmatis, and (3) experimental tests of predictions in M. smegmatis. This will lead to iterative and synergistic feedback between theories/models and experiments. The results of the proposed work are expected to reveal novel evolutionary design principles characterizing relationships between network architecture and dynamical performance across bacterial species, which are essential for the manipulation of naturally occurring networks and for designing synthetic gene circuits.