Slow nucleosome dynamics set the transcriptional speed limit and induce RNA polymerase II traffic jams and bursts.
Slow nucleosome dynamics set the transcriptional speed limit and induce RNA polymerase II traffic jams and bursts.
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DOI：
10.1371/journal.pcbi.1009811
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发表时间：
2022-03
影响因子：
4.3
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Mines RC;Lipniacki T;Shen X
核小体被认为是转录的关键调节因子。然而，缓慢的核小体解包动力学和批量转录特性之间的关系还没有得到彻底的探讨。在这里，我们构建了一个基于代理的模型，我们称之为动态缺陷完全不对称简单排除过程（ddTASEP），以研究核小体诱导的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诱导RNAPII车队形成，这将协同防止核小体重新结合导致转录爆发。平均第一次通过时间（MFPT）和第一次通过时间（VFPT）的方差分析表示的核小体速率常数，允许直接定量的影响核小体诱导的暂停先锋聚合酶动力学。平均首次通过伸长率γ（hc，ho）与MFPT成反比，可视为ddTASEP相图的新轴，与经典αβ平面正交（其中α和β为起始和终止速率）。随后，我们发现，当β = 1时，在αγ平面中存在一种新的干扰跃迁，该跃迁将ddTASEP动力学分离为启动限制区和核小体暂停限制区。我们提出了RNAPII密度ρ，平均延伸率v和转录通量J的分析估计，并进行了数值验证。我们证明，内突发RNAPII等待时间锡遵循的时间车头时距分布的最大流量TASEP和平均突发间隔与分散度的指数De。在极限γ→0中，平均突发大小达到由闭合速率hc设置的最大值。当α ≥ 1时，爆发大小呈几何分布，即使平均爆发大小很小，也允许大爆发。最后，静态和动态缺陷的相对影响的初步结果表明，动态缺陷可以诱导相等或更大的停顿比静态瓶颈。为了执行特定功能，细胞必须通过转录将DNA中的信息复制到RNA中来表达特定基因。被称为核小体的结构蛋白质沿着DNA链的长度每隔沿着200个碱基对间隔开，并且通过紧密结合DNA链并将它们浓缩成异染色质来调节基因活性，从而防止RNA聚合酶II（RNAPII）的转录。即使在核小体松散地附着在DNA链上的活性基因上，当RNAPII经过时，核小体的缠绕和展开也会暂停转录。以前的转录数学模型将这种生物过程与没有障碍物的单车道高速公路上的交通进行了比较。相比之下，我们提出的模型模拟转录一样的交通在网格系统中，核小体可以被认为是行人或其他车辆穿越道路在规则间隔的十字路口。就像小街交通和人行横道可以导致汽车形成车队，并造成堵塞，限制了一个地区的最大速度，核小体可以导致RNAPII形成车队，导致mRNA的生产爆发，并限制了基因的平均聚合酶流量。
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 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 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. To perform specific functions, cells must express specific genes by copying the information in DNA into RNA via transcription. Structural proteins called nucleosomes are spaced every 200 base pairs along the length of a strand of DNA and play a crucial function in the regulation of gene activity by tightly binding DNA strands and condensing them into heterochromatin, preventing transcription by RNA polymerase II (RNAPII). Even on active genes where nucleosomes are loosely attached to DNA strands, the wrapping and unwrapping of nucleosomes pause transcription as RNAPII passes by. Previous mathematical models of transcription have compared this biological process to traffic on a one lane highway without obstructions. In contrast, our proposed model simulates transcription like traffic in a grid system where nucleosomes can be thought of as pedestrians or other vehicles crossing the road at regularly spaced intersections. Just as side street traffic and pedestrian crossings can cause cars to form convoys and cause jams limiting the max speed in an area, nucleosomes can cause RNAPII to form convoys that lead to bursts of mRNA production and limit the average polymerase flux through the gene.
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在单细胞水平上表观遗传调节的动力学。
DOI：
10.1126/science.aab2956
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bintu L;Yong J;Antebi YE;McCue K;Kazuki Y;Uno N;Oshimura M;Elowitz MB
通讯作者：
Elowitz MB
影响因子：
9.3
作者：
Erdmann-Pham, Dan D.;Khanh Dao Duc;Song, Yun S.
通讯作者：
Song, Yun S.
影响因子：
64.8
作者：
Chang, Hannah H.;Hemberg, Martin;Huang, Sui
通讯作者：
Huang, Sui
影响因子：
14.9
作者：
Collings CK;Waddell PJ;Anderson JN
通讯作者：
Anderson JN
影响因子：
16.8
作者：
通讯作者：
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