Regulatory redundancy and its functional consequences in gene networks

生物化学系统通常由明显具有冗余效应的不同机制调节。使用一个独特的工具包模型分析和仿真工具在我的实验室开发了二十年，我将研究冗余调控基因网络，以建立冗余控制的生理作用的理解。冗余可以作为故障保护机制；它可以改变刺激-反应曲线的形状；它还可以影响响应的时间进展，包括其噪声特性。不同的冗余生化机制可能更适合于这些功能中的一个或另一个。我建议对具有不同冗余控制系统的三个重要基因调控系统进行深入研究，以深入了解冗余的动态作用。***Cat-1是一种阳离子氨基酸转运体，负责摄取精氨酸和赖氨酸，赖氨酸是必需氨基酸。氨基酸饥饿导致Cat-1表达上调，这一过程分三个阶段进行：首先，基础水平转录本的翻译被打开，从而实现快速的初始反应；然后，应激反应因子ATF4激活Cat-1基因的转录，使mRNA水平升高；最后，另一种应激反应蛋白XBP1s维持转录反应。这是一个非常复杂的控制系统，有两种不同的途径，翻译和转录，在应激条件下增加表达。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节网络的自适应价值。***细菌经常遇到一氧化氮（NO），这要么是由于哺乳动物的免疫反应，要么是由于它们自身的代谢。由于NO是有毒的，细菌对NO有防御能力。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，它的转录由两个转录抑制因子FNR和NsrR共同控制。在其他细菌中，如色链霉菌，只有NsrR控制Hmp的表达。这些变体将能够直接比较冗余（大肠杆菌）与非冗余（彩色大肠杆菌）控制系统的特性。***脊椎动物体内器官左右不对称的发展取决于Lefty和Nodal两种蛋白质的不对称表达。Nodal是左侧决定因子，而Lefty是Nodal活性的抑制因子。Lefty通过抑制信号转导蛋白Smad2的激活磷酸化来抑制Nodal活性。Lefty以三种不同的方式干扰Smad2磷酸化。这些多余的控制对于左右模式的形成真的是必要的吗？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?