Controlling gene expression timing through gene regulatory architecture.
Controlling gene expression timing through gene regulatory architecture.
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DOI：
10.1371/journal.pcbi.1009745
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发表时间：
2022-01
影响因子：
4.3
通讯作者：
Brewster RC
中科院分区：
文献类型：
--
作者：
Ali MZ;Brewster RC
基因网络通常涉及具有相关功能的多个基因的调控。这种连接性使得能够对基因表达的水平和时间进行相关控制。在这里，我们研究如何在基因的调控 DNA 中编码单输入模块基序中的基因表达时序。使用随机模拟，我们检查了结合亲和力、TF 调节功能和网络大小在控制平均首次传代时间以达到自动调节 TF 基因和靶基因稳态表达的固定分数方面的作用。我们还研究了首次传代时间的变异性如何取决于这些因素。我们发现网络大小和结合亲和力都可以显着加快或减慢网络基因的响应时间，在某些情况下预测与组成型基因相比会发生超过 100 倍的变化。此外，这些因素也会显着影响该响应的保真度。重要的是，这些效应不会发生在网络大小或结合亲和力的“极端”处，而是发生在任一数量的中间窗口中。受调控的基因能够对刺激做出反应，以增加或减少特定蛋白质的产生。尽管人们相当多地关注反应的幅度（或倍数变化）以及它如何取决于调节 DNA 的结构细节，但决定基因反应时间的动力学是 DNA 中编码的基因的另一个关键特征。解开决定基因响应时间和 DNA 编码响应精度的规则提出了一个基本问题。在这篇手稿中，我们系统地研究了自动调节网络中基因的响应时间是如何由网络的分子细节控制的。特别是，我们发现网络大小和 TF 结合亲和力是关键参数，在自动激活的情况下可以减慢自动调节基因的响应时间，或者在自动抑制的情况下加快自动调节 TF 控制的基因的响应时间。此外，我们发现响应的精度很大程度上取决于这些特征。
Gene networks typically involve the regulatory control of multiple genes with related function. This connectivity enables correlated control of the levels and timing of gene expression. Here we study how gene expression timing in the single-input module motif can be encoded in the regulatory DNA of a gene. Using stochastic simulations, we examine the role of binding affinity, TF regulatory function and network size in controlling the mean first-passage time to reach a fixed fraction of steady-state expression for both an auto-regulated TF gene and a target gene. We also examine how the variability in first-passage time depends on these factors. We find that both network size and binding affinity can dramatically speed up or slow down the response time of network genes, in some cases predicting more than a 100-fold change compared to that for a constitutive gene. Furthermore, these factors can also significantly impact the fidelity of this response. Importantly, these effects do not occur at “extremes” of network size or binding affinity, but rather in an intermediate window of either quantity. Regulated genes are able to respond to stimuli in order to ramp up or down production of specific proteins. Although there is considerable focus on the magnitude (or fold-change) of the response and how that depends on the architectural details of the regulatory DNA, the dynamics, which dictates the response time of the gene, is another key feature of a gene that is encoded within the DNA. Unraveling the rules that dictate both the response time of a gene and the precision of that response encoded in the DNA poses a fundamental problem. In this manuscript, we systematically investigate how the response time of genes in auto-regulatory networks is controlled by the molecular details of the network. In particular, we find that network size and TF-binding affinity are key parameters that can slow, in the case of auto-activation, or speed up, in the case of auto-repression, the response time of not only the auto-regulated gene but also the genes that are controlled by the auto-regulated TF. In addition, we find that the precision of the response depends crucially on these characteristics.
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