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

Abstract

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.

Supercoiling-mediated feedback rapidly couples and tunes transcription

“…While we do not directly examine transcription elongation rates, we similarly predict syntax-specific differences in expression dynamics, but observe distinct syntax-specific behaviors in our model [45, 46]. We also find that intergenic distance only weakly affects supercoiling feedback [46]. In alignment with experimental work, we find that positive supercoiling accumulates in the intergenic region of convergently-oriented native genes [38].…”

“…Our prediction of burst dynamics complements theoretical and experimental investigations of cooperative interactions of RNA polymerases arising from the beneficial cancellation of positive and negative supercoiling generated by adjacent polymerases [29, 45]. While we do not directly examine transcription elongation rates, we similarly predict syntax-specific differences in expression dynamics, but observe distinct syntax-specific behaviors in our model [45, 46]. We also find that intergenic distance only weakly affects supercoiling feedback [46].…”

“…Importantly, our selected phenomenological term will stall polymerase motion if either the torque upstream or downstream exceeds the stall torque τ s . Some models choose a stalling equation that only stalls if the difference between the upstream and downstream torque exceeds a stall torque [46]; we chose this form, reasoning that the DNA unwinding and rewinding process opposed, respectively, by upstream and downstream torque could independently stall. When simulated, the difference between these stalling models is small in practice; polymerases at the start or end of the burst encounter both high upstream and downstream torques and a high torque difference, whereas polymerases in the middle of a burst experience both low adjacent torques and a low torque difference.…”

“…Together these data suggest that the process of transcription drives formation of supercoiling-linked, kilobase-scale structures that feedback into transcriptional regulation of gene expression. As supercoiling rapidly diffuses across long distances [43], transcriptional activity at one site may impact the overall activity and dynamics of transcription of proximal genes [44][45][46]. Understanding how supercoiling induces coupling between neighboring genes provides the opportunity to improve the predictable design of transgenic systems from simple reporters to sophisticated dynamic circuits.…”

Collective polymerase dynamics emerge from DNA supercoiling during transcription

“…During the development of this article, two related works with some overlapping results appeared [40, 41]. The first article [40] used an existing model from [15] and the second article makes no explicit connection to DNA mechanics and is largely focused on explaining the recent experimental results that increasing initiation rates can increase elongation rates [4]. In both articles, the connection between elongation kinetics, clustering, and gene expression fluctuations is not made.…”