Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
PLoS Comput Biol. 2022 Feb 10;18(2):e1009811. doi: 10.1371/journal.pcbi.1009811. eCollection 2022 Feb.
Nucleosomes are recognized as key regulators of transcription. However, the relationship between slow nucleosome unwrapping dynamics and bulk transcriptional properties has not been thoroughly explored. Here, an agent-based model that we call the dynamic defect Totally Asymmetric Simple Exclusion Process (ddTASEP) was constructed to investigate the effects of nucleosome-induced pausing on transcriptional dynamics. Pausing due to slow nucleosome dynamics induced RNAPII convoy formation, which would cooperatively prevent nucleosome rebinding leading to bursts of transcription. The mean first passage time (MFPT) and the variance of first passage time (VFPT) were analytically expressed in terms of the nucleosome rate constants, allowing for the direct quantification of the effects of nucleosome-induced pausing on pioneering polymerase dynamics. The mean first passage elongation rate γ(hc, ho) is inversely proportional to the MFPT and can be considered to be a new axis of the ddTASEP phase diagram, orthogonal to the classical αβ-plane (where α and β are the initiation and termination rates). Subsequently, we showed that, for β = 1, there is a novel jamming transition in the αγ-plane that separates the ddTASEP dynamics into initiation-limited and nucleosome pausing-limited regions. We propose analytical estimates for the RNAPII density ρ, average elongation rate v, and transcription flux J and verified them numerically. We demonstrate that the intra-burst RNAPII waiting times tin follow the time-headway distribution of a max flux TASEP and that the average inter-burst interval [Formula: see text] correlates with the index of dispersion De. In the limit γ→0, the average burst size reaches a maximum set by the closing rate hc. When α≪1, the burst sizes are geometrically distributed, allowing large bursts even while the average burst size [Formula: see text] is small. Last, preliminary results on the relative effects of static and dynamic defects are presented to show that dynamic defects can induce equal or greater pausing than static bottle necks.
核小体被认为是转录的关键调节因子。然而，缓慢核小体解缠动力学与整体转录性质之间的关系尚未得到彻底探讨。在这里，我们构建了一个基于代理的模型，称为动态缺陷完全不对称简单排斥过程（ddTASEP），以研究核小体诱导暂停对转录动力学的影响。由于缓慢的核小体动力学引起的暂停导致 RNAPII 车队形成，这将协同阻止核小体重新结合，导致转录爆发。平均首次通过时间（MFPT）和首次通过时间的方差（VFPT）可以用核小体速率常数表示，从而可以直接量化核小体诱导暂停对先驱聚合酶动力学的影响。平均首次通过延伸率γ（hc，ho）与 MFPT 成反比，可以被认为是 ddTASEP 相图的一个新轴，与经典的αβ平面（其中α和β是起始和终止速率）正交。随后，我们表明，对于β=1，在 αγ 平面上存在一个新的堵塞转变，将 ddTASEP 动力学分为起始限制和核小体暂停限制区域。我们提出了关于 RNAPII 密度ρ、平均延伸率 v 和转录通量 J 的解析估计，并进行了数值验证。我们证明了爆发内的 RNAPII 等待时间 tin 遵循最大通量 TASEP 的时间间隔分布，并且平均爆发间间隔[Formula: see text]与分散度 De 相关。在γ→0 的极限下，平均爆发大小达到由闭合速率 hc 设定的最大值。当α≪1 时，爆发大小呈几何分布，即使平均爆发大小[Formula: see text]较小，也允许出现大爆发。最后，给出了静态和动态缺陷相对影响的初步结果，表明动态缺陷可以引起与静态瓶颈相等或更大的暂停。
