How does supercoiling regulation on a battery of RNA polymerases impact on bacterial transcription bursting?

Jing, Xiaobo; Loskot, Pavel; Jin, Yu

doi:10.1088/1478-3975/aad933

Cited by 9 publications

(19 citation statements)

References 43 publications

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“…Several theoretical ideas have been proposed to uncover the microscopic origin of transcriptional bursting (17)(18)(19)(20)(21)(22)(23)(24). One of them suggests that the transcriptional bursting is a result of the collective dynamics of multiple RNA polymerases (RNAP) that move along the DNA chain and catalyze the synthesis of messenger RNA molecules (17).…”

Section: Introductionmentioning

confidence: 99%

“…But the currently dominating opinion in this field is that the transcriptional bursting is a consequence of coupling between chemical and mechanical processes (18)(19)(20)(21)(22)(23)(24). During transcription, the RNAP moves rotationally following the DNA helical chain, unwinding the double-stranded DNA segment in front and reannealing it behind.…”

Section: Introductionmentioning

confidence: 99%

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A Mechanochemical Model of Transcriptional Bursting

Klindziuk

Meadowcroft

Kolomeisky

2020

Biophysical Journal

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Populations of genetically identical cells generally show a large variability in cell phenotypes, which is typically associated with the stochastic nature of gene expression processes. It is widely believed that a significant source of such randomness is the transcriptional bursting, which is when periods of active production of RNA molecules alternate with periods of RNA degradation. However, the molecular mechanisms of such strong fluctuations remain unclear. Recent studies suggest that DNA supercoiling, which happens during transcription, might be directly related to the bursting behavior. Stimulated by these observations, we developed a stochastic mechano-chemical model of supercoiling-induced transcriptional bursting where the RNA synthesis leads to the buildup of torsion in DNA. This slows down the RNA production until binding of an enzyme gyrase to DNA, which releases the stress and allows for the RNA synthesis to restart with the original rate. Using a thermodynamically consistent coupling between mechanical and chemical processes, dynamic properties of transcription are explicitly evaluated. In addition, a first-passage method to evaluate the dynamics of transcription is developed. Theoretical analysis shows that the transcriptional bursting is observed when both the supercoiling and the mechanical stress-release due to gyrase are present in the system. It is also found that the overall RNA production rate is not constant and depends on the number of previously synthesized RNA molecules. A comparison with experimental data on bacteria allows us to evaluate the energetic cost of supercoiling during transcription. It is argued that the relatively weak mechanochemical coupling allows transcription to be regulated most effectively. SIGNIFICANCE Transcriptional bursting has been cited as one of the probable causes of phenotypic differences in cells with identical genomes. However, the microscopic origin of noisy dynamics in RNA production remains unclear. We developed a thermodynamically-consistent mechano-chemical stochastic model, which, via explicit calculations of dynamic properties, provides a consistent physical-chemical description of how the supercoiling of DNA together with enzymatic activity of gyrases produce transcriptional bursting. It also allows us to explain that the coupling between mechanical and chemical processes might be the reason for efficient regulation of transcription.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Mechanochemical Model of Transcriptional Bursting

Klindziuk

Meadowcroft

Kolomeisky

2020

Biophysical Journal

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“…It was assumed also that after the gyrase molecule binds to DNA the mechanical stress is immediately released. However, this probably is not very realistic, and recent experimental measurements (18) and theoretical arguments (23) suggest that the stress relief a relatively slow process. Our theoretical method can be extended to take this effect into account, and we believe that this will not change the main conclusions of our analysis.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanochemical Model of Transcriptional Bursting

Klindziuk

Meadowcroft

Kolomeisky

2019

Preprint

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Populations of genetically identical cells generally show a large variability in cell phenotypes, which is typically associated with the stochastic nature of gene expression processes. It is widely believed that a significant source of such randomness is the transcriptional bursting, which is when periods of active production of RNA molecules alternate with periods of RNA degradation. However, the molecular mechanisms of such strong fluctuations remain unclear. Recent studies suggest that DNA supercoiling, which happens during transcription, might be directly related to the bursting behavior. Stimulated by these observations, we developed a stochastic mechano-chemical model of supercoiling-induced transcriptional bursting where the RNA synthesis leads to the buildup of torsion in DNA. This slows down the RNA production until binding of an enzyme gyrase to DNA, which releases the stress and allows for the RNA synthesis to restart with the original rate. Using a thermodynamically consistent coupling between mechanical and chemical processes, dynamic properties of transcription are explicitly evaluated. In addition, a first-passage method to evaluate the dynamics of transcription is developed. Theoretical analysis shows that the transcriptional bursting is observed when both the supercoiling and the mechanical stress-release due to gyrase are present in the system. It is also found that the overall RNA production rate is not constant and depends on the number of previously synthesized RNA molecules. A comparison with experimental data on bacteria allows us to evaluate the energetic cost of supercoiling during transcription. It is argued that the relatively weak mechanochemical coupling allows transcription to be regulated most effectively.SIGNIFICANCE Transcriptional bursting has been cited as one of the probable causes of phenotypic differences in cells with identical genomes. However, the microscopic origin of noisy dynamics in RNA production remains unclear. We developed a thermodynamically-consistent mechano-chemical stochastic model, which, via explicit calculations of dynamic properties, provides a consistent physical-chemical description of how the supercoiling of DNA together with enzymatic activity of gyrases produce transcriptional bursting. It also allows us to explain that the coupling between mechanical and chemical processes might be the reason for efficient regulation of transcription.

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Two-Phase Dynamics of DNA Supercoiling Based on DNA Polymer Physics Model

Wan

2021

Biophysical Journal

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progression. Transcription of bcl-2 is controlled by two promoters, one of which contains a GQ-forming sequence. Understanding the stabilizing forces in this structure may lead to novel chemotherapeutic design. There are gaps in our current understanding of under what conditions GQs fold, which is crucial information that can give insight into the equilibrium of GQ conformations. To advance our understanding of the dominant bcl-2 promoter GQ, we performed molecular dynamics (MD) simulations using the Drude-2017 polarizable force field. Our simulation outcomes highlight two distinct changes within the GQ that coincide with ion binding. The first is the recruitment of a bulk K þ ion to the solvent-exposed face of the tetrad stem, which led to changes in base dipole moments and the K þ interaction energies of the guanines within the tetrad core. The second is the emergence of an ''electronegative pocket'' between the tetrad core and the long loop below the tetrad core. Ion binding in the electronegative pocket induces a backbone conformational change that may be relevant for inducing local conformational changes at K þ concentrations similar to those found in the cell. These results suggest two different locations within the bcl-2 GQ that may be targeted by small molecules to induce conformational changes.

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How does supercoiling regulation on a battery of RNA polymerases impact on bacterial transcription bursting?

Cited by 9 publications

References 43 publications

A Mechanochemical Model of Transcriptional Bursting

A Mechanochemical Model of Transcriptional Bursting

Mechanochemical Model of Transcriptional Bursting

Two-Phase Dynamics of DNA Supercoiling Based on DNA Polymer Physics Model

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