A Mechanochemical Model of Transcriptional Bursting

Abstract

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 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 mechanochemical model of supercoiling-induced transcriptional bursting in which the RNA synthesis leads to the buildup of torsion in DNA. This slows down the RNA production until it is bound by the 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, the 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 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 might allow transcription to be regulated most effectively.