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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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Appearance of radioactivity in β-galactosidase. Appearance of radioactivity incorporated from the three different mRNA strands, at different times after initiation of translation elongation in the models (lines) and in the measurements (crosses, triangles and circles) [17]. Values of radioactivity are normalized such that the maximum corresponds to 23 radioactive methionines.
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Figure 3: Appearance of radioactivity in β-galactosidase. Appearance of radioactivity incorporated from the three different mRNA strands, at different times after initiation of translation elongation in the models (lines) and in the measurements (crosses, triangles and circles) [17]. Values of radioactivity are normalized such that the maximum corresponds to 23 radioactive methionines.

Mentions: To model this, we simulate the transcription and translation processes of the three sequences [17]. We model the incorporation of radioactive methionines at the same locations as in these sequences. The three model strands differ only in sequence, as in the measurements. During the simulations, we measure the number of incorporated radioactive methionines at the same points in time as in the experiment. Results of our simulations and of the measurements [17] are shown in Figure 3, showing good agreement between model and measurements.


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

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

Appearance of radioactivity in β-galactosidase. Appearance of radioactivity incorporated from the three different mRNA strands, at different times after initiation of translation elongation in the models (lines) and in the measurements (crosses, triangles and circles) [17]. Values of radioactivity are normalized such that the maximum corresponds to 23 radioactive methionines.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Appearance of radioactivity in β-galactosidase. Appearance of radioactivity incorporated from the three different mRNA strands, at different times after initiation of translation elongation in the models (lines) and in the measurements (crosses, triangles and circles) [17]. Values of radioactivity are normalized such that the maximum corresponds to 23 radioactive methionines.
Mentions: To model this, we simulate the transcription and translation processes of the three sequences [17]. We model the incorporation of radioactive methionines at the same locations as in these sequences. The three model strands differ only in sequence, as in the measurements. During the simulations, we measure the number of incorporated radioactive methionines at the same points in time as in the experiment. Results of our simulations and of the measurements [17] are shown in Figure 3, showing good agreement between model and measurements.

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