Noise, Bistability & Beneficial Heterogeneity in the Galactose Signaling Network

描述(申请人提供)：50多年来，发芽酵母中的半乳糖信号网络一直是真核细胞基因调控的范例。在此期间，收集了关于该网络的大量遗传和生化数据，从而对该网络中基因和蛋白质之间的分子相互作用有了几乎完全的了解。然而，尽管有大量关于其分子相互作用的数据，但对其动力学系统行为的先验预测仍然非常具有挑战性。其主要原因在于GAL网络中多个嵌套反馈环的复杂组织，这使得系统动力学分析变得困难。在这个方案中，萌芽酵母的半乳糖信号通路被用作一个模型系统，以发展一个包含多个转录反馈控制的网络的动力学系统特性的详细的定量理解。此外，我们还将探讨这些动力学特性对其生理相关性的影响以及对种群适合度的影响。由于在过去50年中对GAL网络进行了广泛的研究，人们对其主要组成部分和相互作用有了详细的了解，这使该网络成为系统级分析的理想候选者。该建议集中于三个特定的目标，每个目标都反映了随机动力系统的一个重要概念：噪声、双稳和有益的异质性。首先，将探索单个酵母细胞的随机切换动力学作为时间的函数。此外，还将从实验和理论两方面研究开关特性的表观遗传。其次，利用一种新的方法，利用开环网络推导出反馈控制遗传开关的稳定性条件。最后，随机基因表达的生理相关性将通过探索动态异质种群在暴露于波动环境中时是否能够实现比同质种群更高的净增长率来解决。这项工作不仅有助于详细了解GAL网络中的反馈调节及其对基因表达动力学和种群适应度的影响，而且还将提供新的实验和理论技术和概念，这些技术和概念将对高等真核生物的基因网络分析具有重要意义。

DESCRIPTION (provided by applicant): The galactose signaling network in the budding yeast Saccharomyces cerevisiae has been serving as the paradigm for gene regulation in eukaryotic cells for more than 50 years. During this period a wealth of genetic and biochemical data on this network was collected resulting in a nearly complete understanding of the molecular interactions between the genes and proteins in this network. However, despite extensive data on its molecular interactions, an a priori prediction of its dynamical system behavior is still very challenging. The main reason for this lies in the complex organization of multiple nested feedback loops in the GAL network, which makes an analysis of the system dynamics difficult. In this proposal the galactose signaling pathway of the budding yeast Saccharomyces cerevisiae is used as a model system to develop a detailed quantitative understanding of the dynamical system properties of a network containing multiple transcriptional feedback controls. Additionally we will explore what the consequences of these dynamical properties are regarding its physiological relevance and its impact on the fitness of a population. Since the GAL network has been studied extensively during the last five decades a detailed knowledge of its main components and interactions has been developed making this network an ideal candidate for a system-level analysis. The proposal focusses on three specific aims each reflecting an important concept of stochastic dynamical systems: noise, bistability, and beneficial heterogeneity. First, the stochastic switching dynamics of single yeast cells will be explored as a function of time. Additionally, the epigenetic inheritance of the switch properties will be studied both experimentally and theoretically. Second a new method will be used to deduce the stability conditions of a feedback controlled genetic switch by using open loop networks. Finally, the physiological relevance of stochastic gene expression will be addressed by exploring if a dynamically heterogeneous population can achieve a higher net growth rate than a homogenous population when exposed to fluctuating environments. The proposed work will not only lead to a detailed understanding of feedback regulation in the GAL network and its consequences for gene expression dynamics and population fitness, but will also provide novel experimental and theoretical techniques and concepts that will be important for the analysis of gene networks in higher eukaryotes.