Landscape and Global Stability of Nonadiabatic and Adiabatic Oscillations in a Gene Network
Landscape and Global Stability of Nonadiabatic and Adiabatic Oscillations in a Gene Network
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DOI：
10.1016/j.bpj.2012.02.002
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发表时间：
2012-03-07
影响因子：
3.4
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Feng, Haidong;Han, Bo;Wang, Jin
我们量化了潜在的景观，以确定生物振荡的全球稳定性和一致性。我们在我们的实验合成生物学研究中探索了一个基因网络基序，这两个基因通过自我激活和自我抑制相互抑制和激活。我们发现，除了固有的分子数波动之外，还有另一种对生物功能至关重要的波动：蛋白质调节因子与基因启动子缓慢结合/解结合的波动。我们发现相干极限环振荡出现在两种状态：与蛋白质合成/降解相关的具有快速结合/解结合的绝热状态和具有缓慢结合/解结合的非绝热状态。这导致产生稳定振荡的两种机制：在绝热状态下平均基因状态的有效相互作用；而在非绝热状态下，由于启动子结合/解结合缓慢而造成的时间延迟，可以通过即将进行的实验来验证。在这两种情况下，景观在蛋白质浓度上具有墨西哥帽的拓扑形状，定量地决定了极限环动力学的全局稳定性。振荡相干性与墨西哥帽的形状相关，其特征是从振荡环到中央顶部的高度。通过改变结合/解结合速率，振荡周期可以在一个很宽的范围内调节，而不改变幅度，这对生物钟的功能是重要的。由于缓慢的结合/解除结合而产生时间延迟的负反馈回路也会产生振荡。虽然正反馈不是产生振荡所必需的，但它可以使振荡更加鲁棒。
We quantify the potential landscape to determine the global stability and coherence of biological oscillations. We explore a gene network motif in our experimental synthetic biology studies of two genes that mutually repress and activate each other with self-activation and self-repression. We find that in addition to intrinsic molecular number fluctuations, there is another type of fluctuation crucial for biological function: the fluctuation due to the slow binding/unbinding of protein regulators to gene promoters. We find that coherent limit cycle oscillations emerge in two regimes: an adiabatic regime with fast binding/unbinding and a nonadiabatic regime with slow binding/unbinding relative to protein synthesis/degradation. This leads to two mechanisms of producing the stable oscillations: the effective interactions from averaging the gene states in the adiabatic regime; and the time delays due to slow binding/unbinding to promoters in the nonadiabatic regime, which can be tested by forthcoming experiments. In both regimes, the landscape has a topological shape of the Mexican hat in protein concentrations that quantitatively determines the global stability of limit cycle dynamics. The oscillation coherence is shown to be correlated with the shape of the Mexican hat characterized by the height from the oscillation ring to the central top. The oscillation period can be tuned in a wide range by changing the binding/unbinding rate without changing the amplitude much, which is important for the functionality of a biological clock. A negative feedback loop with time delays due to slow binding/unbinding can also generate oscillations. Although positive feedback is not necessary for generating oscillations, it can make the oscillations more robust.