对结合目标的竞争导致激活剂和抑制剂同时作用的矛盾效应 -- 扩展版

M. Ali Al-Radhawi, Krishna Manoj, Dhruv D. Jatkar, Alon Duvall, Domitilla Del Vecchio, Eduardo D. Sontag
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引用次数: 0

摘要

在癌症转移过程中的表观遗传转化方面,最近发现了一种令人费解的效应,即消除(敲除)激活调控因子会导致被调控因子的活性增加(而不是减少)。据推测,这种反常行为可以通过激活和抑制转录因子竞争与其他可能的靶标结合来解释。在哺乳动物细胞中证明这一假设非常困难,因为潜在的参与者众多,而且内源性细胞内调控网络非常复杂。本文通过一个类似的合成生物学结构来分析这一问题,旨在利用标准的细菌基因表达网络重现这一矛盾行为。本文首先回顾了激发癌症生物学研究的工作,然后描述了一个拟议的合成构建。本文建立了一个数学模型,确定了稳态唯一性和向平衡收敛的基本特性,并确定了应导致出现这种悖论现象(更多激活剂导致稳态活性降低)的参数区。此外,还给出了一个证明,表明这是一种稳态特性,对于初始瞬态,将不会观察到这种现象。这项工作为合成电路中资源竞争的一般工作方法增添了新的内容。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Competition for binding targets results in paradoxical effects for simultaneous activator and repressor action -- Extended Version
In the context of epigenetic transformations in cancer metastasis, a puzzling effect was recently discovered, in which the elimination (knock-out) of an activating regulatory element leads to increased (rather than decreased) activity of the element being regulated. It has been postulated that this paradoxical behavior can be explained by activating and repressing transcription factors competing for binding to other possible targets. It is very difficult to prove this hypothesis in mammalian cells, due to the large number of potential players and the complexity of endogenous intracellular regulatory networks. Instead, this paper analyzes this issue through an analogous synthetic biology construct which aims to reproduce the paradoxical behavior using standard bacterial gene expression networks. The paper first reviews the motivating cancer biology work, and then describes a proposed synthetic construct. A mathematical model is formulated, and basic properties of uniqueness of steady states and convergence to equilibria are established, as well as an identification of parameter regimes which should lead to observing such paradoxical phenomena (more activator leads to less activity at steady state). A proof is also given to show that this is a steady-state property, and for initial transients the phenomenon will not be observed. This work adds to the general line of work of resource competition in synthetic circuits.
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