MicroRNAs in target gene upregulation
Even though we have a reasonable understanding of the miRNA regulatory networks, the diversity of miRNA mediated gene expression pattern never fails to surprise. Recent reports suggest that in certain conditions and specific cell types, miRNAs also upregulate target gene expression.15,103 Vasudevan et al103have observed that miR-369-3 upregulates the translation of reporter mRNA with AU-rich elements (ARE) in HeLa and HEK293T cells arrested in the quiescent/G0 phase.103 During serum-starved conditions, microRNP protein known as FXR1 (fragile X mental retardation related protein 1) remains bounded with the AGO2 protein in the RISC complex. This leads to better base pairing between miR-369-3 and ARE, and results in translation upregulation.103 Studies have shown that in liver cells, mir-122 enhances the translation of Hepatitis-C virus (HCV) RNA, which has IRES (internal ribosome entry site) within its 5’UTR. Mengardi et al50 further revealed that binding of any miRNA can enhance the translation of the reporter RNA driven by HCV IRES by inserting let-7 and miR-451 binding sites in the 3’UTR of the HCV RNA.50 Fascinatingly, in ribosomal protein (RP) mRNAs, miR-10a binding sites are present in their 5’UTR region downstream of the 5’ TOP motif, which senses cellular stress and mitogen stimuli and controls RPs translation. Mir-10a enhances the translation of ribosomal proteins after binding to the 5’UTR and increases global protein synthesis, which has the potential for oncogenic transformation of cells.104
These experimental evidences suggest that miRNA can downregulate or upregulate target protein expression depending on the conditions and other given factors. One can envisage that the miRNA mediated target gene repression or upregulation mostly follow a similar mechanism (Fig. 6 ), but the dynamics of the overall process gets altered in a context-specific manner. In this regard, few mathematical models have been developed to explain what leads to such unexpected target protein upregulation by miRNA.84,105
Sengupta et al84 showed a similar upregulation in the expression of E2F1 by mir-17-9284 using a detailed ODE-based mathematical model for Myc/E2F1/mir-17-92 network. In their model, miRNA forms complex with E2F1 mRNA, from which E2F1 mRNA gets degraded. They assumed that the translation can happen from the miRNA bounded E2F1 mRNA, but at a much lower rate than from the free mRNA. They have shown that depending on the degradation rate and the translation efficiency of E2F1 mRNA present in the complex, one can reproduce a scenario where the corresponding miRNA can either repress to upregulate the E2F1 protein expression (Fig. 6 ).84
Nyananit and Gadgil provided a plausible explanation for such target upregulation by using a mathematical model in which multiple miRNAs compete for a single mRNA.105 They created a detailed model for a single mRNA regulated by two miRNAs by considering all the biochemical processes such as transcription, translation, and degradation. In their model, mRNA can form complex with any one of the two available miRNAs and also with both the miRNAs, if the binding sites are not overlapping. From the miRNA: mRNA complex, either the target or the miRNA can get degraded while the other counterpart gets recycled back. All the species in the model has inherent degradation rates. They also assumed that protein translation can happen from both free and miRNA bound mRNA. From simulations, they have observed that an increase in miRNA level always results in decreased protein levels when a single miRNA targets the mRNA. However, when there is combinatorial regulation by two miRNAs and there is an overlapping of the two MREs, such that two miRNAs cannot bind at the same time, they observe an unexpected positive effect of miRNA on target protein abundance in certain parameter space.