Title: Bifurcations and multistability in inducible three-gene toggle switch networks Show Chinese title

Title: 可诱导的三基因切换开关网络中的分岔和多稳定性

Abstract: Control of transcription presides over a vast array of biological processes including through gene regulatory circuits that exhibit multistability. Two- and three-gene network motifs are often found to be critical parts of the repertoire of metabolic and developmental pathways. Theoretical models of these circuits, however, typically vary parameters such as dissociation constants, transcription rates, and degradation rates without specifying precisely how these parameters are controlled biologically. In this paper, we examine the role of effector molecules, which can alter the concentrations of the active transcription factors that control regulation, and are ubiquitous to regulatory processes across biological settings. We specifically consider allosteric regulation in the context of extending the standard bistable switch to three-gene networks, and explore the rich multistable dynamics exhibited in these architectures as a function of effector concentrations. We then study how the conditions required for tristability and more complex dynamics, and the bifurcations in dynamic phase space upon tuning effector concentrations, evolve under various interpretations of regulatory circuit mechanics, the underlying activity of inducers, and perturbations thereof. Notably, the biological mechanism by which we model effector control over dual-function proteins transforms not only the phenotypic trend of dynamic tuning but also the set of available dynamic regimes. In this way, we determine key parameters and regulatory features that drive phenotypic decisions, and offer an experimentally tunable structure for encoding inducible multistable behavior arising from both single and dual-function allosteric transcription factors. Show Chinese abstract

Abstract: 转录控制主导着包括基因调控回路在内的大量生物过程，这些回路表现出多稳态特性。 二基因和三基因网络模体通常被认为是代谢和发育通路的重要组成部分。 然而，这些电路的理论模型通常会改变诸如解离常数、转录速率和降解速率等参数，但并未明确说明这些参数在生物学上是如何被控制的。 在本文中，我们研究了效应分子的作用，这些分子可以改变控制调控的活性转录因子的浓度，并且在各种生物环境中都是调控过程的普遍特征。 我们特别考虑在扩展标准双稳态开关至三基因网络的背景下，别构调控的作用，并探讨这些结构在效应分子浓度函数下的丰富多稳态动态特性。 然后，我们研究了在不同调控电路机械解释、诱导物的基本活性及其扰动下，实现三稳态和更复杂动态所需的条件以及在调节效应分子浓度时动态相空间中的分岔如何演变。 值得注意的是，我们对效应分子控制双功能蛋白的生物学机制的建模不仅改变了动态调节的表型趋势，还改变了可用动态区域的集合。 通过这种方式，我们确定了驱动表型决策的关键参数和调控特征，并提供了一种可实验调节的结构，用于编码由单功能和双功能别构转录因子引起的可诱导多稳态行为。