Abstract
microRNAs (miRNAs) are small noncoding RNAs that are important post-transcriptional regulators of gene expression. miRNAs can induce thresholds in protein synthesis. Such thresholds in protein output can be also achieved by oligomerization of transcription factors (TF) for the control of gene expression. First, we propose a minimal model for protein expression regulated by miRNA and by oligomerization of TF. We show that miRNA and oligomerization of TF generate a buffer, which increases the robustness of protein output towards molecular noise as well as towards random variation of kinetics parameters. Next, we extend the model by considering that the same miRNA can bind to multiple messenger RNAs, which accounts for the dynamics of a minimal competing endogenous RNAs (ceRNAs) network. The model shows that, through common miRNA regulation, TF can control the expression of all proteins formed by the ceRNA network, even if it drives the expression of only one gene in the network. The model further suggests that the threshold in protein synthesis mediated by the oligomerization of TF can be propagated to the other genes, which can increase the robustness of the expression of all genes in such ceRNA network. Furthermore, we show that a miRNA could increase the time delay of a “Goodwin-like” oscillator model, which may favor the occurrence of oscillations of large amplitude. This result predicts important roles of miRNAs in the control of the molecular mechanisms leading to the emergence of biological rhythms. Moreover, a model for the latter oscillator embedded in a ceRNA network indicates that the oscillatory behavior can be propagated, via the shared miRNA, to all proteins formed by such ceRNA network. Thus, by means of computational models, we show that miRNAs could act as vectors allowing the propagation of robustness in protein synthesis as well as oscillatory behaviors within ceRNA networks.
Highlights
MicroRNAs are short noncoding RNA molecules of 20–30 nucleotides, which can bind to the 39 UTR of messenger RNA resulting in a post-transcriptional repression of protein synthesis by targeting the corresponding messenger RNA for degradation and/or by inhibiting its translation [1,2].Besides the key role of miRNAs for the down-regulation of protein expression [3,4,5], miRNAs can induce thresholds in protein synthesis [6]
In order to assess only the effect of miRNA and oligomerization of transcription factors (TF) on protein synthesis, the model does not incorporate any assumptions about feedback and feed-forward regulations between the miRNA and its target gene [41]
MiRNAs and their target genes are often embedded in feedback and feed-forward regulatory motifs, which may improve the robustness of protein expression towards molecular noise [10,41]
Summary
Besides the key role of miRNAs for the down-regulation of protein expression [3,4,5], miRNAs can induce thresholds in protein synthesis [6] They are often involved in feedforward regulations with their target genes, allowing an increase in the robustness of protein expression towards molecular noise [6,7,8,9,10,11]. MiRNAs could act as oncogenes or tumor suppressors and are able to control critical steps in cancer development [14,15,16,17,18,19,20], such as the process of cell transformation [21] and the epithelial-to-mesenchymal transition (EMT transition) [22,23,24]. The latter transition is crucial for the initiation and the development of metastasis. miRNAs are involved in molecular regulatory networks driving cell differentiation in multiple tissues [15,25,26,27]
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