Regulatory redundancy and its functional consequences in gene networks

生化系统通常由不同的机制调节，具有明显的冗余效应。使用我实验室二十多年来开发的模型分析和模拟工具的独特工具包，我将研究冗余调控的基因网络，以了解冗余控制的生理作用。冗余可以作为一种故障安全机制;它可以改变刺激-反应曲线的形状;它还可以影响反应的时间进程，包括其噪声特性。不同的生化冗余机制可能更适合于这些功能中的一个或另一个。我建议对三个重要的基因调控系统进行深入研究，这些系统具有不同的冗余控制系统，以深入了解冗余的动力学作用。Cat-1是一种阳离子氨基酸转运蛋白，负责摄取精氨酸和赖氨酸，后者是必需氨基酸。氨基酸饥饿导致Cat-1表达上调，分为三个阶段：首先，在基础水平表达的转录本的翻译被打开，这使得快速的初始反应成为可能;然后，应激反应因子ATF 4激活Cat-1基因的转录，提高mRNA水平;最后，第二种应激反应蛋白XBP 1 s起维持转录反应的作用。这是一个非常复杂的控制系统，有两个不同的途径，翻译和转录，在胁迫条件下增加表达。我们将通过模拟Cat-1在各种营养环境中的表达和运输活性来研究这种调控网络的适应性价值。细菌经常遇到一氧化氮（NO），无论是由于哺乳动物的免疫反应，或由于他们自己的新陈代谢。由于NO是有毒的，细菌对NO有防御作用。在许多细菌中，主要的NO解毒酶是Hmp。Hmp仅在NO存在下合成。在大肠杆菌中，其转录由两个转录抑制因子FNR和NsrR共同控制。在其他细菌如天蓝色链霉菌中，只有NsrR控制Hmp的表达。这些变量将使冗余（E。coli）与非冗余（S. coelicolor）控制系统。*脊椎动物内脏器官左右不对称性的形成依赖于两种蛋白质Lefty和Nodal的不对称表达。Nodal是左侧决定子，而Lefty是Nodal活性的抑制子。Lefty通过抑制信号转导蛋白Smad 2的活化磷酸化来抑制Nodal活性。Lefty以三种不同的方式干扰Smad 2磷酸化。这些多余的控制真的是左右方向图形成所必需的吗？如果不是，是什么进化压力维持了这种冗余？

Biochemical systems are often regulated by distinct mechanisms with apparently redundant effects. Using a unique toolkit of model analysis and simulation tools developed in my lab over two decades, I will study redundantly regulated gene networks to build an understanding of the physiological roles of the redundant controls. Redundancy can act as a failsafe mechanism; it can change the shape of a stimulus-response curve; it can also affect the temporal progression of a response, including its noise characteristics. Different biochemical mechanisms of redundancy may be better suited to one or another of these functions. I propose to make an intensive study of three important gene regulatory systems with different redundant control systems to develop insights into the dynamical roles of the redundancies.***Cat-1 is a cationic amino acid transporter responsible for uptake of arginine and lysine, the latter an essential amino acid. Amino acid starvation results in upregulation of Cat-1 expression, proceeding in three phases: first, the translation of transcripts expressed at basal levels is turned on, which enables a rapid initial response; then, the stress-response factor ATF4 activates the transcription of the Cat-1 gene, ramping up mRNA levels; finally, a second stress-response protein, XBP1s, acts to sustain the transcriptional response. This is a very complex control system, with two distinct pathways, translational and transcriptional, for increasing expression under stress conditions. We will study this regulatory network's adaptive value by modelling the expression and transport activity of Cat-1 in a variety of nutritional environments.***Bacteria frequently encounter nitric oxide (NO), either due to the mammalian immune response, or due to their own metabolism. Since NO is toxic, bacteria have defences against NO. In many bacteria, the main NO detoxification enzyme is Hmp. Hmp is only synthesized in the presence of NO. In Escherichia coli, its transcription is controlled jointly by two transcriptional repressors, FNR and NsrR. In other bacteria such as Streptomyces coelicolor, only NsrR controls the expression of Hmp. These variants will enable a direct comparison of the characteristics of redundant (E. coli) vs non-redundant (S. coelicolor) control systems.***The development of internal-organ left-right asymmetry in vertebrates depends on the asymmetric expression of two proteins named Lefty and Nodal. Nodal is a left-side determinant, while Lefty is a suppressor of Nodal activity. Lefty suppresses Nodal activity by inhibiting the activating phosphorylation of the signal transduction protein Smad2. Lefty acts in three different ways to interfere with Smad2 phosphorylation. Are these redundant controls truly necessary for left-right pattern formation? If not, what evolutionary pressures sustain this redundancy?