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

Mäkelä J, Lloyd-Price J, Yli-Harja O, Ribeiro AS - BMC Bioinformatics (2011)

Bottom Line: Finally, modeling sequence-specific transcriptional pauses, we find that these affect protein noise levels.For 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, FI-33101 Tampere, Finland.

ABSTRACT

Background: In 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.

Results: First, 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.

Conclusions: For 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.

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Normalized maximum correlation between RNA and protein time series. The higher the rate of translation initiation (and thus higher protein degradation to keep the mean the same), the more correlated the fluctuations in protein and RNA levels become, as measured by the normalized maximum correlation. This is because the protein levels follow any fluctuations in the RNA levels faster. Similarly, increasing the rate of transcription initiation, while maintaining the rate of translation initiation constant, decreases the correlation between fluctuations in protein and RNA levels.
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Figure 6: Normalized maximum correlation between RNA and protein time series. The higher the rate of translation initiation (and thus higher protein degradation to keep the mean the same), the more correlated the fluctuations in protein and RNA levels become, as measured by the normalized maximum correlation. This is because the protein levels follow any fluctuations in the RNA levels faster. Similarly, increasing the rate of transcription initiation, while maintaining the rate of translation initiation constant, decreases the correlation between fluctuations in protein and RNA levels.

Mentions: From these results, we conclude that the degree of coupling between transcription and translation is likely to be a key determining factor of the noise in protein levels. This can be verified by computing the normalized maximum correlation between time-series of protein and mRNA levels for each set of parameter values (Figure 6). Comparing Figures 5 and 6, we see that higher correlation values are obtained for the regime of higher noise in the protein levels. This implies that the principal source of this noise is the fluctuations in RNA levels.


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

Mäkelä J, Lloyd-Price J, Yli-Harja O, Ribeiro AS - BMC Bioinformatics (2011)

Normalized maximum correlation between RNA and protein time series. The higher the rate of translation initiation (and thus higher protein degradation to keep the mean the same), the more correlated the fluctuations in protein and RNA levels become, as measured by the normalized maximum correlation. This is because the protein levels follow any fluctuations in the RNA levels faster. Similarly, increasing the rate of transcription initiation, while maintaining the rate of translation initiation constant, decreases the correlation between fluctuations in protein and RNA levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113936&req=5

Figure 6: Normalized maximum correlation between RNA and protein time series. The higher the rate of translation initiation (and thus higher protein degradation to keep the mean the same), the more correlated the fluctuations in protein and RNA levels become, as measured by the normalized maximum correlation. This is because the protein levels follow any fluctuations in the RNA levels faster. Similarly, increasing the rate of transcription initiation, while maintaining the rate of translation initiation constant, decreases the correlation between fluctuations in protein and RNA levels.
Mentions: From these results, we conclude that the degree of coupling between transcription and translation is likely to be a key determining factor of the noise in protein levels. This can be verified by computing the normalized maximum correlation between time-series of protein and mRNA levels for each set of parameter values (Figure 6). Comparing Figures 5 and 6, we see that higher correlation values are obtained for the regime of higher noise in the protein levels. This implies that the principal source of this noise is the fluctuations in RNA levels.

Bottom Line: Finally, modeling sequence-specific transcriptional pauses, we find that these affect protein noise levels.For 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computational Systems Biology Research Group, Department of Signal Processing, Tampere University of Technology, FI-33101 Tampere, Finland.

ABSTRACT

Background: In 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.

Results: First, 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.

Conclusions: For 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.

Show MeSH
Related in: MedlinePlus