Tunability enhancement of gene regulatory motifs through competition for regulatory protein resources
Tunability enhancement of gene regulatory motifs through competition for regulatory protein resources
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DOI：
10.1103/physreve.102.052410
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发表时间：
2020-11-24
影响因子：
2.4
通讯作者：
Choubey, Sandeep
中科院分区：
文献类型：
--
作者：
Das, Swetamber;Choubey, Sandeep
基因调控网络（GRNs）协调基因表达的时空水平，从而调节从胚胎发育到组织稳态的各种细胞功能。一些被称为“模体”的模式在GRNs中反复出现。由于这些基序的普遍存在，它们在理解细胞决策和工程合成电路的背景下受到了大量研究。越来越多的实验证据表明，（1）与这些基序相关的基因的拷贝数不同，（2）由这些基因产生的蛋白质与基因组上的诱饵结合位点以及驱动其他基因表达的启动子结合。这两个过程共同引起细胞内蛋白质资源的竞争。为了揭示蛋白质资源的竞争如何影响调控基序的动力学性质，我们提出了一个简单的动力学模型，明确纳入拷贝数变异（CNV）的基因和蛋白质的诱饵结合。使用准稳态近似，我们从理论上研究了三个常见的图案的瞬态和稳态特性：自动调节，拨动开关，和repressilator。虽然蛋白质资源竞争改变了所有这些基序达到稳定状态的时间尺度，但拨动开关和阻遏物的动力学性质以多种方式受到影响。对于切换开关，如果一组蛋白质比另一组蛋白质更频繁地与诱饵结合，则已知吸引子的吸引池会发生显着改变，这种效果随着切换开关的拷贝数增加而受到抑制。对于阻遏蛋白，蛋白质共享导致出现振荡的参数空间区域，以前nonoscillating。有趣的是，振荡的幅度和频率都通过CNV和诱饵结合的相互作用以非线性方式改变。总的来说，细胞内蛋白质资源的竞争提供了基因调控基序的额外调控层。
Gene regulatory networks (GRNs) orchestrate the spatiotemporal levels of gene expression, thereby regulating various cellular functions ranging from embryonic development to tissue homeostasis. Some patterns called "motifs" recurrently appear in the GRNs. Owing to the prevalence of these motifs they have been subjected to much investigation, both in the context of understanding cellular decision making and engineering synthetic circuits. Mounting experimental evidence suggests that (1) the copy number of genes associated with these motifs varies, and (2) proteins produced from these genes bind to decoy binding sites on the genome as well as promoters driving the expression of other genes. Together, these two processes engender competition for protein resources within a cell. To unravel how competition for protein resources affects the dynamical properties of regulatory motifs, we propose a simple kinetic model that explicitly incorporates copy number variation (CNV) of genes and decoy binding of proteins. Using quasi-steady-state approximations, we theoretically investigate the transient and steady-state properties of three of the commonly found motifs: Autoregulation, toggle switch, and repressilator. While protein resource competition alters the timescales to reach the steady state for all these motifs, the dynamical properties of the toggle switch and repressilator are affected in multiple ways. For toggle switch, the basins of attraction of the known attractors are dramatically altered if one set of proteins binds to decoys more frequently than the other, an effect which gets suppressed as the copy number of the toggle switch is enhanced. For repressilators, protein sharing leads to an emergence of oscillation in regions of parameter space that were previously nonoscillatory. Intriguingly, both the amplitude and frequency of oscillation are altered in a nonlinear manner through the interplay of CNV and decoy binding. Overall, competition for protein resources within a cell provides an additional layer of regulation of gene regulatory motifs.