ABSTRACTPopulations 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.SIGNIFICANCETranscriptional 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.
Integrating nuclear receptor mobility in models of gene regulation
