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1. Nucleosomes play a dual role in regulating transcription dynamics

   https://doi.org/10.1073/pnas.2319772121  

   Brahmachari, Sumitabha; Tripathi, Shubham; Onuchic, José N; Levine, Herbert (July 2024, Proceedings of the National Academy of Sciences)

   Transcription has a mechanical component, as the translocation of the transcription machinery or RNA polymerase (RNAP) on DNA or chromatin is dynamically coupled to the chromatin torsion. This posits chromatin mechanics as a possible regulator of eukaryotic transcription, however, the modes and mechanisms of this regulation are elusive. Here, we first take a statistical mechanics approach to model the torsional response of topology-constrained chromatin. Our model recapitulates the experimentally observed weaker torsional stiffness of chromatin compared to bare DNA and proposes structural transitions of nucleosomes into chirally distinct states as the driver of the contrasting torsional mechanics. Coupling chromatin mechanics with RNAP translocation in stochastic simulations, we reveal a complex interplay of DNA supercoiling and nucleosome dynamics in governing RNAP velocity. Nucleosomes play a dual role in controlling the transcription dynamics. The steric barrier aspect of nucleosomes in the gene body counteracts transcription via hindering RNAP motion, whereas the chiral transitions facilitate RNAP motion via driving a low restoring torque upon twisting the DNA. While nucleosomes with low dissociation rates are typically transcriptionally repressive, highly dynamic nucleosomes offer less of a steric barrier and enhance the transcription elongation dynamics of weakly transcribed genes via buffering DNA twist. We use the model to predict transcription-dependent levels of DNA supercoiling in segments of the budding yeast genome that are in accord with available experimental data. The model unveils a paradigm of DNA supercoiling-mediated interaction between genes and makes testable predictions that will guide experimental design. 

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

   https://doi.org/10.1093/nar/gkab1252  

   Tripathi, Shubham; Brahmachari, Sumitabha; Onuchic, José N.; Levine, Herbert (December 2021, Nucleic Acids Research)

   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. 

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3. Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization

   https://doi.org/10.1038/s41467-024-48698-z  

   Kant, Aayush; Guo, Zixian; Vinayak, Vinayak; Neguembor, Maria Victoria; Li, Wing Shun; Agrawal, Vasundhara; Pujadas, Emily; Almassalha, Luay; Backman, Vadim; Lakadamyali, Melike; et al (December 2024, Nature Communications)

   Abstract In interphase nuclei, chromatin forms dense domains of characteristic sizes, but the influence of transcription and histone modifications on domain size is not understood. We present a theoretical model exploring this relationship, considering chromatin-chromatin interactions, histone modifications, and chromatin extrusion. We predict that the size of heterochromatic domains is governed by a balance among the diffusive flux of methylated histones sustaining them and the acetylation reactions in the domains and the process of loop extrusion via supercoiling by RNAPII at their periphery, which contributes to size reduction. Super-resolution and nano-imaging of five distinct cell lines confirm the predictions indicating that the absence of transcription leads to larger heterochromatin domains. Furthermore, the model accurately reproduces the findings regarding how transcription-mediated supercoiling loss can mitigate the impacts of excessive cohesin loading. Our findings shed light on the role of transcription in genome organization, offering insights into chromatin dynamics and potential therapeutic targets. 

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4. Density- and elongation speed-dependent error correction in RNA polymerization

   https://doi.org/10.1088/1478-3975/ac45e2  

   Zuo, Xinzhe; Chou, Tom (January 2022, Physical Biology)

   Abstract Backtracking of RNA polymerase (RNAP) is an important pausing mechanism during DNA transcription that is part of the error correction process that enhances transcription fidelity. We model the backtracking mechanism of RNAP, which usually happens when the polymerase tries to incorporate a noncognate or ‘mismatched’ nucleotide triphosphate. Previous models have made simplifying assumptions such as neglecting the trailing polymerase behind the backtracking polymerase or assuming that the trailing polymerase is stationary. We derive exact analytic solutions of a stochastic model that includes locally interacting RNAPs by explicitly showing how a trailing RNAP influences the probability that an error is corrected or incorporated by the leading backtracking RNAP. We also provide two related methods for computing the mean times for error correction and incorporation given an initial local RNAP configuration. Using these results, we propose an effective interacting-RNAP lattice that can be readily simulated. 

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5. An Accurate and Stable Filtered Explicit Scheme for Biopolymerization Processes in the Presence of Perturbations

   Davis, L. (November 2021, Applied and computational mathematics)

   The focus of this paper is the development, numerical simulation and parameter analysis of a model of the transcription of ribosomal RNA in highly transcribed genes. Inspired by the well-known classic Lighthill-Whitham-Richards (LWR) traffic flow model, a linear advection continuum model is used to describe the DNA transcription process. In this model, elongation velocity is assumed to be essentially constant as RNA polymerases move along the strand through different phases of gene transcription. One advantage of using the linear model is that it allows one to quantify how small perturbations in elongation velocity and inflow parameters affect important biology measures such as Average Transcription Time (ATT) for the gene. The ATT per polymerase is the amount of time an individual RNAP spends traveling through the DNA strand. The numerical treatment for model simulations includes introducing a low complexity and time accurate method by adding a simple linear time filter to the classic upwind scheme. This improved method is modular and requires a minimal modification of adding only one line of code resulting in increased accuracy without increased computational expense. In addition, it removes the overdamping of upwind. A stability condition for the new algorithm is derived, and numerical computations illustrate stability and convergence of the filtered scheme as well as improved ATT estimation. 

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