论文标题
基因开关的随机表观遗传动力学
Stochastic epigenetic dynamics of gene switching
论文作者
论文摘要
组蛋白的表观遗传学修饰至关重要地影响真核基因的活性,而表观遗传组蛋白状态在很大程度上取决于特定因子(例如转录因子(TFS))与DNA的结合。在这里,当TF合成受组蛋白状态调节时,TFS和组蛋白状态的动态相关方式并不明显。这种反馈调节关系在基因网络中无处不在,以确定分化和其他细胞转换中的细胞命运。为了了解这种动态反馈法规,我们理论上通过将反应动力学的DOI-PELITI操作员形式上扩展到耦合分子过程问题来分析表观遗传基因转换的模型。引入了SPIN-1和SPIN-1/2相干状态表示,以描述组蛋白的随机反应以及TF的结合/解键统一的方式,从而简明了这些分子过程中时间尺度差异的影响;即使在TF与DNA的结合/解开的情况下,绝热是快速的,缓慢的非绝热组蛋白动力学也会在基因态分布的景观中围绕盆地周围盆地的概率通量的明显圆流流动,从而导致基因开关的滞后性。与普遍认为,TF量的变化在组蛋白状态发生变化之前的一般信念相反,通量驱动组蛋白在自调节电路中TF量变化之前进行修改。 Flux-Landscape分析表明了表观遗传细胞命运决策的非线性非绝热机制。
Epigenetic modifications of histones crucially affect the eukaryotic gene activity, while the epigenetic histone state is largely determined by the binding of specific factors such as the transcription factors (TFs) to DNA. Here, the way how the TFs and the histone state are dynamically correlated is not obvious when the TF synthesis is regulated by the histone state. This type of feedback regulatory relations are ubiquitous in gene networks to determine cell fate in differentiation and other cell transformations. To gain insights into such dynamical feedback regulations, we theoretically analyze a model of epigenetic gene switching by extending the Doi-Peliti operator formalism of reaction kinetics to the problem of coupled molecular processes. The spin-1 and spin-1/2 coherent state representations are introduced to describe stochastic reactions of histones and binding/unbinding of TF in a unified way, which provides a concise view of the effects of timescale difference among these molecular processes; even in the case that binding/unbinding of TF to/from DNA are adiabatically fast, the slow nonadiabatic histone dynamics give rise to a distinct circular flow of the probability flux around basins in the landscape of the gene state distribution, which leads to hysteresis in gene switching. In contrast to the general belief that the change in the amount of TF precedes the histone state change, the flux drives histones to be modified prior to the change in the amount of TF in the self-regulating circuits. The flux-landscape analyses shed light on the nonlinear nonadiabatic mechanism of epigenetic cell fate decision making.