Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins
Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins
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DOI：
10.1529/biophysj.106.096891
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发表时间：
2007-05-10
影响因子：
3.4
通讯作者：
Byrne, John H.
中科院分区：
文献类型：
--
作者：
Song, Hao;Smolen, Paul;Byrne, John H.
cAMP-反应元件结合（CREB）蛋白参与许多细胞过程中的转录调节（例如，例如，在一个实施例中，神经可塑性和昼夜节律）。CREB家族包含激活子和抑制子，它们可以通过正反馈环和负反馈环相互作用。这些环可以通过CREB蛋白表达的自动和交叉调节，经由其基因中或附近的CRE元件产生。实验表明，这种反馈回路可以在几个系统中运行（例如，例如，在一个实施例中，和大鼠）。为了理解通过转录的交叉调节互锁的这种反馈环的功能含义，开发了具有正环和负环的最小模型，并使用分叉分析进行了研究。分叉分析揭示了不同的非线性动力学（e。例如，在一个实施例中，双稳态和振荡）。稳态或振荡的稳定性可以通过激活剂（CREB 1）或阻遏物（CREB 2）合成中的时间延迟来改变。随机的调查。由于CREB 1和CREB 2的小分子数的波动揭示了CREB分子在双稳态区域中的双峰分布。CREB表达的稳定高和低状态对随机噪声的鲁棒性不同，并且需要临界数量的分子来维持高状态数天或更长时间。增加正反馈或减少负反馈也增加了高状态的寿命，这种状态的持续可能与长期记忆的形成有关。还需要临界数量的分子来维持CREB表达的强烈振荡。如果一个定常状态接近一个确定性的Hopf分岔点，随机共振可以诱导振荡。这种确定性和随机动力学的比较分析，不仅提供了CREB监管基序的可能的动态的见解，但也展示了一个框架，了解其他监管过程与类似的网络架构。
cAMP- response element binding ( CREB) proteins are involved in transcriptional regulation in a number of cellular processes ( e. g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross- regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems ( e. g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross- regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics ( e. g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator ( CREB1) or the repressor ( CREB2). Investigation of stochastic. uctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.