Karapetyan Sargis, Buchler Nicolas E
Department of Physics, Duke University, Durham, North Carolina 27708, USA.
Center for Genomic & Computational Biology, Durham, North Carolina 27710, USA.
Phys Rev E Stat Nonlin Soft Matter Phys. 2015 Dec;92(6):062712. doi: 10.1103/PhysRevE.92.062712. Epub 2015 Dec 22.
Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ultrasensitivity that is specific for repression. We then use stochastic simulation to show that multiple binding sites increase the coherence of oscillations by mitigating the binary noise. Slow values of DNA unbinding rate are also effective in alleviating molecular noise due to the increased distance from the bifurcation point. Our work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, can have a significant impact on the temporal and stochastic dynamics of genetic oscillators.
遗传振荡器，如生物钟，不断受到基因调控中涉及的少量分子产生的分子噪声的干扰。随机性最强的来源之一是二元噪声，它源于调节蛋白与染色体DNA中启动子的结合。在本研究中，我们聚焦于基于激活剂滴定和阻遏剂滴定的两种最小振荡器，以了解对振荡和克服二元噪声至关重要的关键参数。我们表明，尽管传统上认为从DNA上解离的速率是一个快速参数，但它需要缓慢才能拓宽振荡解的空间。添加多个独立的DNA结合位点进一步扩展了阻遏剂滴定振荡器的振荡参数空间，并延长了两个振荡器的周期。这种效应是由于多个结合位点导致的解离动力学有效延迟增加以及阻遏特异性的启动子超敏感性增加的综合结果。然后，我们使用随机模拟表明，多个结合位点通过减轻二元噪声增加了振荡的相干性。由于与分岔点的距离增加，DNA解离速率的缓慢值在减轻分子噪声方面也很有效。我们的工作证明了基因回路生物物理模型中经常被忽略的DNA结合位点数量和缓慢的解离动力学如何对遗传振荡器的时间和随机动力学产生重大影响。
