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Major role for mRNA stability in shaping the kinetics of gene induction.

Elkon R, Zlotorynski E, Zeller KI, Agami R - BMC Genomics (2010)

Bottom Line: In particular, kinetic waves in transcriptional responses are usually interpreted as resulting from sequential activation of transcription factors.Such effect cannot be explained even by a complete shut-off of transcription, and therefore indicates intense modulation of RNA stability.Taken together, our results demonstrate the key role of mRNA stability in determining induction kinetics in mammalian transcriptional networks.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. r.elkon@nki.nl

ABSTRACT

Background: mRNA levels in cells are determined by the relative rates of RNA production and degradation. Yet, to date, most analyses of gene expression profiles were focused on mechanisms which regulate transcription, while the role of mRNA stability in modulating transcriptional networks was to a large extent overlooked. In particular, kinetic waves in transcriptional responses are usually interpreted as resulting from sequential activation of transcription factors.

Results: In this study, we examined on a global scale the role of mRNA stability in shaping the kinetics of gene response. Analyzing numerous expression datasets we revealed a striking global anti-correlation between rapidity of induction and mRNA stability, fitting the prediction of a kinetic mathematical model. In contrast, the relationship between kinetics and stability was less significant when gene suppression was analyzed. Frequently, mRNAs that are stable under standard conditions were very rapidly down-regulated following stimulation. Such effect cannot be explained even by a complete shut-off of transcription, and therefore indicates intense modulation of RNA stability.

Conclusion: Taken together, our results demonstrate the key role of mRNA stability in determining induction kinetics in mammalian transcriptional networks.

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Related in: MedlinePlus

Global relationship between mRNA stability and kinetics of gene induction. For each dataset described in Additional file 1, we compared the T half-life distribution between early- and late- induced genes (that is, between genes that responded above the fold-change threshold specified in Additional file 1 before or at the 2 h time point and those that were induced later than 2 h). Numbers of early- and late-induced genes in each dataset are specified below the respective box-plots. (p-values were calculated using Wilcoxon test).
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Figure 3: Global relationship between mRNA stability and kinetics of gene induction. For each dataset described in Additional file 1, we compared the T half-life distribution between early- and late- induced genes (that is, between genes that responded above the fold-change threshold specified in Additional file 1 before or at the 2 h time point and those that were induced later than 2 h). Numbers of early- and late-induced genes in each dataset are specified below the respective box-plots. (p-values were calculated using Wilcoxon test).

Mentions: Next, we examined the generality of the association between kinetics of induction and RNA stability. We analyzed a variety of time-course expression datasets recorded in human and murine cells, collectively covering many different aspects of cellular physiology. In the vast majority of the datasets analyzed, we found a highly significant anti-correlation between rapidity of induction and mRNA stability (Figure 3, Additional file 1, Additional file 2). This widespread relationship points to the critical role played by mRNA stability in shaping the dynamics of gene induction in complex transcriptional networks. It also indicates a broad conservation of RNA stability under different conditions, which therefore reflects, to a large extent, an intrinsic property of the mRNA molecules. Inspection of the early-induced genes revealed a core set of genes whose induction-response was very rapid in many different datasets and which encode highly unstable transcripts (e.g., Fos, Jun, Ier3, Dusp1, Atf3, Btg2 and Zfp36; all have T half-life lower than 1 hr). (Additional file 3 lists the core set genes, defined as the set of genes that were induced before or at 2 hrs after stimulation in at least three of the six datasets recorded in murine cells.) However, the broad relationship between mRNA stability and induction kinetics is not merely explained by this common core set of rapidly induced genes, as the relationship remained highly significant also after the removal of this core set from the analysis (Additional file 4, data not shown). This indicates that many other genes with an unstable mRNA were rapidly induced in a stimulus-specific manner.


Major role for mRNA stability in shaping the kinetics of gene induction.

Elkon R, Zlotorynski E, Zeller KI, Agami R - BMC Genomics (2010)

Global relationship between mRNA stability and kinetics of gene induction. For each dataset described in Additional file 1, we compared the T half-life distribution between early- and late- induced genes (that is, between genes that responded above the fold-change threshold specified in Additional file 1 before or at the 2 h time point and those that were induced later than 2 h). Numbers of early- and late-induced genes in each dataset are specified below the respective box-plots. (p-values were calculated using Wilcoxon test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864252&req=5

Figure 3: Global relationship between mRNA stability and kinetics of gene induction. For each dataset described in Additional file 1, we compared the T half-life distribution between early- and late- induced genes (that is, between genes that responded above the fold-change threshold specified in Additional file 1 before or at the 2 h time point and those that were induced later than 2 h). Numbers of early- and late-induced genes in each dataset are specified below the respective box-plots. (p-values were calculated using Wilcoxon test).
Mentions: Next, we examined the generality of the association between kinetics of induction and RNA stability. We analyzed a variety of time-course expression datasets recorded in human and murine cells, collectively covering many different aspects of cellular physiology. In the vast majority of the datasets analyzed, we found a highly significant anti-correlation between rapidity of induction and mRNA stability (Figure 3, Additional file 1, Additional file 2). This widespread relationship points to the critical role played by mRNA stability in shaping the dynamics of gene induction in complex transcriptional networks. It also indicates a broad conservation of RNA stability under different conditions, which therefore reflects, to a large extent, an intrinsic property of the mRNA molecules. Inspection of the early-induced genes revealed a core set of genes whose induction-response was very rapid in many different datasets and which encode highly unstable transcripts (e.g., Fos, Jun, Ier3, Dusp1, Atf3, Btg2 and Zfp36; all have T half-life lower than 1 hr). (Additional file 3 lists the core set genes, defined as the set of genes that were induced before or at 2 hrs after stimulation in at least three of the six datasets recorded in murine cells.) However, the broad relationship between mRNA stability and induction kinetics is not merely explained by this common core set of rapidly induced genes, as the relationship remained highly significant also after the removal of this core set from the analysis (Additional file 4, data not shown). This indicates that many other genes with an unstable mRNA were rapidly induced in a stimulus-specific manner.

Bottom Line: In particular, kinetic waves in transcriptional responses are usually interpreted as resulting from sequential activation of transcription factors.Such effect cannot be explained even by a complete shut-off of transcription, and therefore indicates intense modulation of RNA stability.Taken together, our results demonstrate the key role of mRNA stability in determining induction kinetics in mammalian transcriptional networks.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. r.elkon@nki.nl

ABSTRACT

Background: mRNA levels in cells are determined by the relative rates of RNA production and degradation. Yet, to date, most analyses of gene expression profiles were focused on mechanisms which regulate transcription, while the role of mRNA stability in modulating transcriptional networks was to a large extent overlooked. In particular, kinetic waves in transcriptional responses are usually interpreted as resulting from sequential activation of transcription factors.

Results: In this study, we examined on a global scale the role of mRNA stability in shaping the kinetics of gene response. Analyzing numerous expression datasets we revealed a striking global anti-correlation between rapidity of induction and mRNA stability, fitting the prediction of a kinetic mathematical model. In contrast, the relationship between kinetics and stability was less significant when gene suppression was analyzed. Frequently, mRNAs that are stable under standard conditions were very rapidly down-regulated following stimulation. Such effect cannot be explained even by a complete shut-off of transcription, and therefore indicates intense modulation of RNA stability.

Conclusion: Taken together, our results demonstrate the key role of mRNA stability in determining induction kinetics in mammalian transcriptional networks.

Show MeSH
Related in: MedlinePlus