Stochastic sequence-level model of coupled transcription and translation in prokaryotes

Jarno Mäkelä,Jason Lloyd-Price,Andre S Ribeiro,Olli Yli-Harja

doi:10.1186/1471-2105-12-121

Jarno Mäkelä, Jason Lloyd-Price + Show 2 more

Open Access

https://doi.org/10.1186/1471-2105-12-121

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Abstract

BackgroundIn prokaryotes, transcription and translation are dynamically coupled, as the latter starts before the former is complete. Also, from one transcript, several translation events occur in parallel. To study how events in transcription elongation affect translation elongation and fluctuations in protein levels, we propose a delayed stochastic model of prokaryotic transcription and translation at the nucleotide and codon level that includes the promoter open complex formation and alternative pathways to elongation, namely pausing, arrests, editing, pyrophosphorolysis, RNA polymerase traffic, and premature termination. Stepwise translation can start after the ribosome binding site is formed and accounts for variable codon translation rates, ribosome traffic, back-translocation, drop-off, and trans-translation.ResultsFirst, we show that the model accurately matches measurements of sequence-dependent translation elongation dynamics. Next, we characterize the degree of coupling between fluctuations in RNA and protein levels, and its dependence on the rates of transcription and translation initiation. Finally, modeling sequence-specific transcriptional pauses, we find that these affect protein noise levels.ConclusionsFor parameter values within realistic intervals, transcription and translation are found to be tightly coupled in Escherichia coli, as the noise in protein levels is mostly determined by the underlying noise in RNA levels. Sequence-dependent events in transcription elongation, e.g. pauses, are found to cause tangible effects in the degree of fluctuations in protein levels.

Highlights

In prokaryotes, transcription and translation are dynamically coupled, as the latter starts before the former is complete
Using realistic parameter values extracted from measurements, we address the following questions: how different are the distributions of time intervals between translation initiation events and between translation completion events, i.e., how stochastic is translation elongation? To what extent do fluctuations in temporal RNA levels propagate to temporal protein levels, and what physical parameters control this propagation of noise between the two? we investigate whether transcriptional pauses have a significant effect on the dynamics of protein levels
Parameter values were obtained from measurements in E. coli for LacZ, since the dynamics of transcription and translation have been extensively studied for this gene

Summary

Introduction

Transcription and translation are dynamically coupled, as the latter starts before the former is complete. To study how events in transcription elongation affect translation elongation and fluctuations in protein levels, we propose a delayed stochastic model of prokaryotic transcription and translation at the nucleotide and codon level that includes the promoter open complex formation and alternative pathways to elongation, namely pausing, arrests, editing, pyrophosphorolysis, RNA polymerase traffic, and premature termination. Stepwise translation can start after the ribosome binding site is formed and accounts for variable codon translation rates, ribosome traffic, backtranslocation, drop-off, and trans-translation. In prokaryotes, both transcription and translation are stochastic, multi-stepped processes that involve many components and chemical interactions. One example is sequence-dependent transcriptional pausing [1] When they occur, these events can affect the degree of fluctuations of RNA and protein levels. Recent evidence suggests that these noise sources may be key for bacterial adaptability in unpredictable or fluctuating environmental conditions [11,12]

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