Genetic noise control via protein oligomerization
Genetic noise control via protein oligomerization
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DOI：
10.1186/1752-0509-2-94
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发表时间：
2008-11-03
影响因子：
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通讯作者：
Almaas, Eivind
中科院分区：
文献类型：
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作者：
Ghim, Cheol-Min;Almaas, Eivind
背景：细胞中的基因表达需要在不同的时间尺度上发生随机反应事件。因此，经常导致表型和群体动态后果的分子噪声对生化信号传导设置了基本限制。虽然已经有许多研究将细胞反应网络的结构与噪音耐受性联系起来，但在了解蛋白质-蛋白质相互作用的动态作用方面所做的努力有限。结果：我们开发了一个完全随机的模型，用于正反馈控制单个基因，以及一对基因（切换开关），整合了之前体内和体外研究的定量结果。特别是，我们明确占蛋白质，RNA聚合酶和DNA的启动子/操作序列之间的快速结合-解结合动力学。我们发现，整体噪声水平降低，噪声的频率内容是显着转移到生理上不相关的高频率制度的蛋白质二聚化的存在下。这是独立的选择单体或二聚体作为转录因子，并持续在整个多模型拓扑结构考虑。对于切换开关，我们还发现，蛋白质二聚体的存在下，无论是同源二聚体或异源二聚体，可能会显着降低其随机切换率。因此，二聚体通过防止未诱导（诱导）状态随机诱导（未诱导）来促进稳定的开关功能。结论：调节蛋白之间的特异性结合提供了一种缓冲，可以防止遗传活性波动的传播。缓冲区的容量是结合-解离速率的非单调函数。由于蛋白质寡聚化本身不需要额外的蛋白质组分被表达，因此它为快速控制内在或外在噪声提供了基础。一般而言，调节回路和表观遗传记忆的稳定性对有机体的适应性有直接影响。我们的研究结果还表明，合成基因电路的设计与可调的鲁棒性为广泛的工程目的的可能途径。
Background: Gene expression in a cell entails random reaction events occurring over disparate time scales. Thus, molecular noise that often results in phenotypic and population-dynamic consequences sets a fundamental limit to biochemical signaling. While there have been numerous studies correlating the architecture of cellular reaction networks with noise tolerance, only a limited effort has been made to understand the dynamic role of protein-protein interactions.Results: We have developed a fully stochastic model for the positive feedback control of a single gene, as well as a pair of genes (toggle switch), integrating quantitative results from previous in vivo and in vitro studies. In particular, we explicitly account for the fast binding-unbinding kinetics among proteins, RNA polymerases, and the promoter/operator sequences of DNA. We find that the overall noise-level is reduced and the frequency content of the noise is dramatically shifted to the physiologically irrelevant high-frequency regime in the presence of protein dimerization. This is independent of the choice of monomer or dimer as transcription factor and persists throughout the multiple model topologies considered. For the toggle switch, we additionally find that the presence of a protein dimer, either homodimer or heterodimer, may significantly reduce its random switching rate. Hence, the dimer promotes the robust function of bistable switches by preventing the uninduced (induced) state from randomly being induced (uninduced).Conclusion: The specific binding between regulatory proteins provides a buffer that may prevent the propagation of fluctuations in genetic activity. The capacity of the buffer is a non-monotonic function of association-dissociation rates. Since the protein oligomerization per se does not require extra protein components to be expressed, it provides a basis for the rapid control of intrinsic or extrinsic noise. The stabilization of regulatory circuits and epigenetic memory in general is of direct implications to organism fitness. Our results also suggest possible avenues for the design of synthetic gene circuits with tunable robustness for a wide range of engineering purposes.