Collective polymerase dynamics emerge from DNA supercoiling during transcription

Abstract

All biological processes ultimately come from physical interactions. The mechanical properties of DNA play a critical role in transcription. RNA polymerase can over or under twist DNA (referred to as DNA supercoiling) when it moves along a gene resulting in mechanical stresses in DNA that impact its own motion and that of other polymerases. For example, when enough supercoiling accumulates, an isolated polymerase halts and transcription stops. DNA supercoiling can also mediate non-local interactions between polymerases that shape gene expression fluctuations. Here, we construct a comprehensive model of transcription that captures how RNA polymerase motion changes the degree of DNA supercoiling which in turn feeds back into the rate at which polymerases are recruited and move along the DNA. Surprisingly, our model predicts that a group of three or more polymerases move together at a constant velocity and sustain their motion (forming what we call a polymeton) whereas one or two polymerases would have halted. We further show that accounting for the impact of DNA supercoiling on both RNA polymerase recruitment and velocity recapitulates empirical observations of gene expression fluctuations. Finally, we propose a mechanical toggle switch whereby interactions between genes are mediated by DNA twisting as opposed to proteins. Understanding the mechanical regulation of gene expression provides new insights into how endogenous genes can interact and informs the design of new forms of engineered interactions.PACS numbers:

Supercoiling-mediated feedback rapidly couples and tunes transcription

“…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].…”

“…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.…”

A spatially resolved stochastic model reveals the role of supercoiling in transcription regulation

“…We showed that the cooperation between RNAP molecules, manifested by the enhancement in elongation rate in highly expressed genes, is mediated by supercoiling cancellation and the consequently reduced torque generated by RNAP. It is noteworthy that previous models [20,26,28] treat the supercoiling diffusion between topological barriers as an infinitely fast process. However, by explicitly modeling supercoiling diffusion, we showed that the actual diffusion coefficient matters.…”

“…Although supercoiling is proposed to mediate the communication between multiple RNAP molecules and multiple genes, it is not clear how supercoiling dynamics lead to changes in transcription activities quantitatively and how these changes are dependent on the mechanical properties of DNA and the transcription kinetics of RNAP. Several models [20,21,22,23,24,25,26,27,28] have been established to explore the role of supercoiling in transcription regulation. However, none of these models fully captured the complex interactions between transcription and supercoiling.…”

“…However, none of these models fully captured the complex interactions between transcription and supercoiling. Instead, they mainly focused on a subset of key aspects, such as the contribution of supercoiling to transcription initiation [21,23,24,26] or elongation [20,22,25,27] only, and supercoiling diffusion was not explicitly modeled [28]. Here we present a spatially resolved, chemical master-equation based model of E. coli transcription that explicitly describes all stages of transcription (initiation, elongation, and termination, Fig 1A -1C), and their interplay with DNA supercoiling and other cellular processes that regulate DNA torsional stress (topoisomerase activity, supercoiling diffusion, and the dynamical formation and dissociation of topological domains, Fig 1D -1G).…”