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bioRxiv · 10.1101/2025.05.26.655193

Topoisomerase Based Control of Cellular Transcription and Growth

Clark, H. K.·Yeung, E.·Thirumaligai, R.·Giusto, C.
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Abstract

Global cellular transcription and growth are tightly coupled to the supercoiling state of a cells genomic DNA. Direct processes that modulate the supercoiling state of genomic DNA thus provide a novel mechanistic route for biological control of cellular dynamics. In this work, we develop a stochastic model of genome-wide transcriptional responses to local DNA supercoiling and show that, despite heterogeneity in the transcription of each individual gene, the overall system converges to a unique stationary distribution. From the stochastic system, we derive a corresponding nonlinear population model with both local and global supercoiling states, demonstrate that the proposed model exhibits a unique, globally stable equilibrium point, and identify key parameters through sensitivity analysis. We further extend the model by considering the temperature-sensitive gyrase mutant E. coli strain nalA43 and illustrate how shifting the gyrase-topoisomerase balance via temperature acts as an effective control knob on the population, from which we derive a control law. Numerical simulations confirm the effectiveness of the derived control law and provide insight into the dynamics of the system. These results help establish a theoretical foundation for understanding the crucial equilibrium dynamics of topoisomerase enzymes and their implications for cell function.

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Clark, H. K., Yeung, E., Thirumaligai, R., Giusto, C.. 2025-05-28. Topoisomerase Based Control of Cellular Transcription and Growth. https://doi.org/10.1101/2025.05.26.655193

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