Added value of autoregulation and multi-step kinetics of transcription initiation.

Mahendra Kumar Prajapat,Andre S Ribeiro

doi:10.1098/rsos.181170

Mahendra Kumar Prajapat, Andre S Ribeiro

Open Access

https://doi.org/10.1098/rsos.181170

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Abstract

Bacterial gene expression regulation occurs mostly during transcription, which has two main rate-limiting steps: the close complex formation, when the RNA polymerase binds to an active promoter, and the subsequent open complex formation, after which it follows elongation. Tuning these steps' kinetics by the action of e.g. transcription factors, allows for a wide diversity of dynamics. For example, adding autoregulation generates single-gene circuits able to perform more complex tasks. Using stochastic models of transcription kinetics with empirically validated parameter values, we investigate how autoregulation and the multi-step transcription initiation kinetics of single-gene autoregulated circuits can be combined to fine-tune steady state mean and cell-to-cell variability in protein expression levels, as well as response times. Next, we investigate how they can be jointly tuned to control complex behaviours, namely, time counting, switching dynamics and memory storage. Overall, our finding suggests that, in bacteria, jointly regulating a single-gene circuit's topology and the transcription initiation multi-step dynamics allows enhancing complex task performance.

Highlights

Bacterial cells can tune their gene expression profile in response to environmental changes [1,2,3,4,5,6,7,8]
We model gene expression when constitutive and when externally or autoregulated by activator/repressor transcription factor (TF), which act on transcription initiation
The cell-to-cell variability in protein numbers is affected, which is expected because higher tprior/Dt allows more frequent binding and unbinding of the RNA polymerases (RNAPs) to the active promoters in between transcription events

Summary

Introduction

Bacterial cells can tune their gene expression profile in response to environmental changes [1,2,3,4,5,6,7,8]. E.g. in Escherichia coli, this adaptability is made possible by, among other things, fine-tuning the transcription kinetics of its genes [9]. This is enhanced by the multi-step nature of transcript initiation [10,11,12,13], whose steps can be individually or jointly controlled by promoter-specific external signals (e.g. transcription factors), global regulators such as s factors, etc.

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