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Kinetics effects and modeling of mRNA turnover

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Broader comprehension of gene expression regulatory mechanisms can be gained from a global analysis of how transcription and degradation are coordinated to orchestrate complex cell responses. The role of messenger RNA (mRNA) turnover modulation in gene expression levels has become increasingly recognized. From such perspective, in this review we briefly illustrate how a simple but effective mathematical model of mRNA turnover and some experimental findings, may together shed light on the molecular mechanisms underpinning the major role of mRNA decay rates in shaping the kinetics of gene activation and repression. WIREs RNA 2015, 6:327–336. doi: 10.1002/wrna.1277 This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability
Two plausible biological mechanisms to generate waves of sequentially induced genes. (a) Sequentially induced genes are generated by a single transcription factor working in concert with a stability ‘gradient’. The timing of expression peaks is modulated by a posttranscriptional regulation where early induced genes are those with a low half‐life value and late induced ones are those with an high half‐life value. (b) The timing of expression peaks is modulated by a cascade of transcription factors (serial regulation). It is plain that both mechanisms (and possibly others) may well be active.
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In silico experiments to illustrate some basic features of gene induction kinetics. The reference time profile with unity steady‐state is plotted in black. The ‘ON’ and ‘OFF’ regions correspond to the turning ‘ON’ or ‘OFF’ of the promoter activity. (a) Induction kinetic of transcripts having the same half‐life value and, therefore, the same response speed. The higher (or lower) steady‐state value of the red and blue time profiles is due only to an increased (or decreased) transcription rate. (b) Induction kinetic of transcripts having different half‐lives. The time profile plotted in red corresponds to an unstable transcript. It shows a faster induction and relaxation profile but a lower steady‐state value. By contrast, the blue one has an higher half‐life value, resulting in a higher steady‐state value but a slower response. The example illustrates that, to obtain both a fast response and an high steady‐state value, the regulatory strategy must destabilize transcriptionally upregulated genes. Panel (c) makes clear that to obtain a faster response while maintaining the same steady‐state value, the cell must increases both transcription and degradation rates (a ‘counteracting’ strategy).
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Comparison among independent yeast mRNA half‐lives genome‐wide measurements. (a) Scatterplot of the Wang dataset versus the Grigull dataset. (b) Scatterplot of the Wang dataset versus the Munchel dataset. As also noted by Munchel et al., the scatterplots show a very low correlation between the various studies. Such disagreement might be the result of the profound effect on cellular physiology of the transcriptional inhibition block used to measure half‐lives.
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The counteracting and synergistic regulatory coordination strategy. The stability/folding diagrams, introduced by Shalem et al. show the log‐normalized change in mRNA stability (x‐axis) plotted against the maximal expression log‐fold change (y‐axis). The counteracting strategy (panel a and b, left inset) requires that induced genes are destabilized and repressed genes are stabilized (negative correlation), whereas the synergistic strategy (panel a and b, right inset) requires that induced genes are stabilized and repressed genes are destabilized (positive correlation). We used estimated half‐life values.
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Periodic behavior of half‐life values during the reproductive and metabolic cell cycle in yeast. Estimated messenger average half‐life values corresponding to genes having the same expression peak timing are reported on the x‐axis. (a) Reproductive cell cycle and (b) yeast metabolic cycle. In both datasets the maximal average half‐life is attained for genes induced during late M phase, including the metabolic cycle and the minimal average half‐life is attained at the early G1 phase.
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