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Register a new userTranscription-driven DNA Supercoiling: Non-Equilibrium Dynamics and Action-at-a-distance
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Added by
Yair Augusto Gutierrez Fosado
Publication date
2019
fields
Physics
and research's language is
English
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We study the effect of transcription on the kinetics of DNA supercoiling in 3D by means of Brownian dynamics simulations of a single nucleotide resolution coarse-grained model for double stranded DNA. By accounting for the action of a transcribing RNA polymerase (RNAP), we characterise the geometry and non equilibrium dynamics of the twin supercoiling domains forming on each side of the RNAP. Textbook pictures depict such domains as symmetric, with plectonemes (writhed DNA) appearing close to the RNAP. On the contrary, we find that the twist generated by transcription results in asymmetric domains, with plectonemes formed far from the RNAP. We show that this translates into an action-at-a-distance on DNA-binding proteins: for instance, positive supercoils downstream of an elongating RNAP destabilise nucleosomes long before the transcriptional machinery reaches the histone octamer. To understand these observations we use our framework to quantitatively analyse the relaxation dynamics of supercoiled DNA. We find a striking separation of timescales between twist diffusion, which is a simple and fast process, and writhe relaxation, which is slow and entails multiple steps.
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We propose a stochastic model for gene transcription coupled to DNA supercoiling, where we incorporate the experimental observation that polymerases create supercoiling as they unwind the DNA helix, and that these enzymes bind more favourably to regions where the genome is unwound. Within this model, we show that when the transcriptionally induced flux of supercoiling increases, there is a sharp crossover from a regime where torsional stresses relax quickly and gene transcription is random, to one where gene expression is highly correlated and tightly regulated by supercoiling. In the latter regime, the model displays transcriptional bursts, waves of supercoiling, and up-regulation of divergent or bidirectional genes. It also predicts that topological enzymes which relax twist and writhe should provide a pathway to down-regulate transcription. This article has been published in Physical Review Letters, May 2016.
We analyse transcriptional bursting within a stochastic non-equilibrium model which accounts for the coupling between the dynamics of DNA supercoiling and gene transcription. We find a clear signature of bursty transcription when there is a separation between the timescales of transcription initiation and supercoiling dissipation - the latter may either be diffusive or mediated by topological enzymes, such as type I or type II topoisomerases. In multigenic DNA domains we observe either bursty transcription, or transcription waves; the type of behaviour can be selected for by controlling gene activity and orientation. In the bursty phase, the statistics of supercoiling fluctuations at the promoter are markedly non-Gaussian.
Transcription is the first step of gene expression, in which a particular segment of DNA is copied to RNA by the enzyme RNA polymerase (RNAP). Despite many details of the complex interactions between DNA and RNA synthesis disclosed experimentally, much of physical behavior of transcription remains largely unknown. Understanding torsional mechanics of DNA and RNAP together with its nascent RNA and RNA-bound proteins in transcription maybe the first step towards deciphering the mechanism of gene expression. In this study, based on the balance between viscous drag on RNA synthesis and torque resulted from untranscribed supercoiled DNA template, a simple model is presented to describe mechanical properties of transcription. With this model, the rotation and supercoiling density of the untranscribed DNA template are discussed in detail. Two particular cases of transcription are considered, transcription with constant velocity and transcription with torque dependent velocity. Our results show that, during the initial stage of transcription, rotation originated from the transcribed part of DNA template is mainly released by the rotation of RNAP synthesis. During the intermediate stage, the rotation is usually released by both the supercoiling of the untranscribed part of DNA template and the rotation of RNAP synthesis, with proportion depending on the friction coefficient in environment and the length of nascent RNA. However, with the approaching to the upper limit of twisting of the untranscribed DNA template, the rotation resulted from transcription will then be mainly released by the rotation of RNAP synthesis.
We perform a spatially resolved simulation study of an AND gate based on DNA strand displacement using several lengths of the toehold and the adjacent domains. DNA strands are modelled using a coarse-grained dynamic bonding model {[}C. Svaneborg, Comp. Phys. Comm. 183, 1793 (2012){]}. We observe a complex transition path from the initial state to the final state of the AND gate. This path is strongly influenced by non-ideal effects due to transient bubbles revealing undesired toeholds and thermal melting of whole strands. We have also characterized the bound and unbound kinetics of single strands, and in particular the kinetics of the total AND operation and the three distinct distinct DNA transitions that it is based on. We observe a exponential kinetic dependence on the toehold length of the competitive displacement operation, but that the gate operation time is only weakly dependent on both the toehold and adjacent domain length. Our gate displays excellent logical fidelity in three input states, and quite poor fidelity in the fourth input state. This illustrates how non-ideality can have very selective effects on fidelity. Simulations and detailed analysis such as those presented here provide molecular insights into strand displacement computation, that can be also be expected in chemical implementations.
A 2015 experiment by Hanson and Delft colleagues provided further confirmation that the quantum world violates the Bell inequalities, being the first Bell test to close two known experimental loopholes simultaneously. The experiment was also taken to provide new evidence of spooky action at a distance. Here we argue for caution about the latter claim. The Delft experiment relies on entanglement swapping, and our main claim is that this geometry introduces an additional loophole in the argument from violation of the Bell inequalities to action at a distance: the apparent action at a distance may be an artifact of collider bias. In the absence of retrocausality, the sensitivity of such experiments to this Collider Loophole (CL) depends on the temporal relation between the entanglement swapping measurement C and the two measurements A and B between which we seek to infer a causal connection. CL looms large if the C is in the future of A and B, but not if C is in the past. The Delft experiment itself is the intermediate case, in which the separation is spacelike. We argue that this leaves it vulnerable to CL, unable to establish conclusively that it avoids it. An Appendix discusses the implications of permitting retrocausality for the issue of causal influence across entanglement swapping measurements.
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