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.