Slow nucleosome dynamics set the transcriptional speed limit and induce RNA polymerase II traffic jams and bursts

Abstract

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 tIBI¯ 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 NB¯ 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.

Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization

“…First, we built a stochastic model to describe Pol II occupancy and dynamics at a gene using a standard Totally Asymmetric Simple Exclusion Process (TASEP) 64–66 . In this model (Fig.…”

Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

“…Mathematical modeling suggests that the burst is associated with a convoy of RNA polymerases released into the gene body producing a region of nucleosome free DNA (Figure 3A). [74] How this process is regulated in important during development, where release is frequently synchronized across a range of genes to coordinate their expression. The timing of each transcriptional burst is critical as the cell cycle may be as short as 2-3 h during some stages of embryogenesis, with changes in chromatin state occurring rapidly [75][76][77] (Figure 1A, Support for the dynamic regulation of transcription is emerging from cryo-electron microscopy studies of the interactions between RNA polymerase and nucleosomes.…”

Studies of the Mechanism of Nucleosome Dynamics: A Review on Multifactorial Regulation from Computational and Experimental Cases

“…Therefore, revealing the regulatory mechanism of nucleosome dynamics may help to understand the disease and therapy. Current studies have shown that the regulatory factors of nucleosomes include histone modification, DNA methylation [ 31 , 36 , 37 ], and the intervention of nucleosome-interacting factors [ 38 , 39 ], as shown in Table 1 . The dynamic modes of nucleosomes and the factors that affect these modes have already been reviewed from different aspects [ 40 , 41 ], and it has been suggested that the dynamic features of nucleosomes are often regulated by these factors, which are jointly and closely involved in genome regulation.…”