A Mechanochemical Model of Transcriptional Bursting

Klindziuk, Alena; Meadowcroft, Billie; Kolomeisky, Anatoly B.

doi:10.1016/j.bpj.2020.01.017

Cited by 13 publications

(16 citation statements)

References 26 publications

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“…Note that in agreement with previous experimental ( 2 ) and theoretical studies ( 39 , 40 ), transcription in our model occurs in bursts ( Supplementary Figure S9 ). Additionally, gene transcription is accompanied by the deposition of positive supercoiling in the DNA downstream of the gene body and negative supercoiling upstream of the TSS ( Supplementary Figure S10 ).…”

Section: Resultssupporting

confidence: 93%

DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases

Tripathi

Brahmachari

Onuchic

et al. 2021

Nucleic Acids Research

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Multiple RNA polymerases (RNAPs) transcribing a gene have been known to exhibit collective group behavior, causing the transcription elongation rate to increase with the rate of transcription initiation. Such behavior has long been believed to be driven by a physical interaction or ‘push’ between closely spaced RNAPs. However, recent studies have posited that RNAPs separated by longer distances may cooperate by modifying the DNA segment under transcription. Here, we present a theoretical model incorporating the mechanical coupling between RNAP translocation and the DNA torsional response. Using stochastic simulations, we demonstrate DNA supercoiling-mediated long-range cooperation between co-transcribing RNAPs. We find that inhibiting transcription initiation can slow down the already recruited RNAPs, in agreement with recent experimental observations, and predict that the average transcription elongation rate varies non-monotonically with the rate of transcription initiation. We further show that while RNAPs transcribing neighboring genes oriented in tandem can cooperate, those transcribing genes in divergent or convergent orientations can act antagonistically, and that such behavior holds over a large range of intergenic separations. Our model makes testable predictions, revealing how the mechanical interplay between RNAPs and the DNA they transcribe can govern transcriptional dynamics.

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Section: Resultssupporting

confidence: 93%

DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases

Tripathi

Brahmachari

Onuchic

et al. 2021

Nucleic Acids Research

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show abstract

“…The supercoiling-mediated, long-range cooperation between RNAPs reported here is in contrast to the short-range cooperation via a physical “push” [16, 17] which has been postulated for a while. Our model also captures the DNA supercoiling-mediated transcription bursting described in previous experimental and theoretical studies [11, 18, 19]. The transcription-supercoiling interplay has further been shown to dictate the organization of bacterial chromosomes into spatial domains, with highly expressed genes forming the boundaries between chromosomal domains [15, 20].…”

Section: Figmentioning

confidence: 76%

“…The supercoiling-mediated, long-range cooperation between RNAPs reported here is in contrast to the short-range cooperation via a physical "push" [16,17] which has been postulated for a while. Our model also captures the DNA supercoiling-mediated transcription bursting described in previous experimental and theoretical studies [11,18,19]. DNA supercoiling-mediated effects can alter the mean RNA production rate when the rate of RNAP recruitment is high.…”

mentioning

confidence: 85%

DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases

Tripathi

Brahmachari

Onuchic

et al. 2021

Preprint

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During transcription elongation, an RNA polymerase II (RNAP) negatively supercoils (untwists) the DNA upstream and positively supercoils (overtwists) the DNA downstream. The resultant torsional stress in the DNA, if not relaxed quickly, can interfere with the RNAP movement. Here, we present a theoretical model incorporating coupling between RNAP translocation and the DNA torsional response which predicts the RNAP velocity profile under DNA stretching and twisting. Using stochastic simulations, we demonstrate long-distance cooperation between multiple RNAPs and show that inhibiting transcription initiation can slow down the already recruited RNAPs, in agreement with recent experimental findings. We predict that the average transcription elongation rate varies non-monotonically with the rate of transcription initiation. We further show that while RNAPs transcribing neighboring genes oriented in tandem can cooperate, those transcribing genes in divergent or convergent orientations can act antagonistically, and that such behavior holds over a large range of intergenic separations. Our model makes testable predictions, providing important insights into the mechanical control of a key cellular process.

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“…While classical models of transcription attribute bursting to promoter dynamics where the promoter switches between an ON and OFF state [26,27,[56][57][58][59], the ddTASEP model exhibits…”

Section: Features Of Nucleosome-induced Convoy Formation and Transcri...mentioning

confidence: 99%

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

Mines

Lipniacki²,

Shen³

2022

PLoS Comput Biol

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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.

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A Mechanochemical Model of Transcriptional Bursting

Cited by 13 publications

References 26 publications

DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases

DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases

DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases

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

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