Introduction
Micro RNAs (miRNAs) are endogenous, non-coding RNA molecules of very
short length (~22 nucleotides), which are normally
involved in gene silencing at the posttranscriptional
level.1–4 They bind to the target mRNA molecules with
complementary sites and inhibit their target protein synthesis via two
modes: (i) by degrading the target mRNA and (ii) by reducing the
translation from the respective mRNA.2,5,6 MicroRNAs
were first discovered in C. elegans by Lee and his
colleagues7 in 1993 and now thousands of microRNAs
have been identified in various species and deposited in online sequence
depositories like miRbase database.6,8 A particular
miRNA can target many mRNAs. Conversely, a single mRNA can be regulated
by multiple miRNAs.9,10 Hence, several computational
algorithms and methods have been developed to identify putative miRNA
targets, which are later validated using
experiments.11 These studies unraveled that more than
two-thirds of the human coding genes get regulated by miRNAs in
different ways. Not only that, miRNAs confer robustness in noisy target
gene expression,12,13 fine-tunes cellular
decision-making events,14 and even upregulates target
gene expression15,16 under specific circumstances.
Thus, understanding miRNA mediated gene expression for a specific
biological network or a process is a challenging task, due to this
diverse nature of miRNA regulation.
Importantly, miRNAs are involved in several gene regulatory networks and
control many cellular processes such as proliferation, differentiation,
apoptosis, metabolism, invasiveness, etc., to influence cell-fate
decisions.4,11,12,17,18 Several studies have shown
that mutations or aberrant expression of miRNAs or components involved
in miRNA biogenesis and regulation are associated with cancer
development and progression.19–22 Thus, miRNAs are
often found to be either oncogenic or tumor suppressors in a
context-dependent manner.19,20,22,23 The abnormality
in miRNA expression could arise due to gene
amplification,24–26 deletion, or
translocation27–29 of the genomic loci with miRNA
genes. Even the miRNA genes can be subjected to epigenetic modifications
like protein-coding genes. In many cancers, epigenetic silencing of
miRNA genes that may act as tumor suppressors has led to
cancer.30–34 Studies have shown that epigenetic
modification of miRNA genes could serve as potential biomarkers for
cancer diagnosis and progression.30,33,34 This
suggests that miRNA affects the proliferation response of cells in more
than one way. Thus, the formation of a defective miRNA or a
malfunctional miRNA can be potentially fatal for a living cell.
Dysregulation of enzymes involved in the miRNA biogenesis pathway
(Fig.1 ) such as Dicer, Drosha, DGCR8, and Exportin, which are
required for miRNA maturation and transportation can further lead to
defective miRNA synthesis and localization.35–37 Once
synthesized, miRNAs are loaded along with ribonucleoproteins like Ago to
form a complex called RNA-induced silencing complex (RISC), which
directs and facilitates the binding of miRNA to the 3’UTR binding site
in the target mRNA. Any mutation in Ago proteins leads to impaired miRNA
regulation.38,39 Another important alteration that can
affect miRNA function is the presence of single nucleotide polymorphisms
(SNPs), and mutations in the miRNA binding site of the
mRNA.40,41 Such mutations can affect the miRNA: miRNA
pairing and make the mRNAs insensitive to the
miRNA19,42 On the contrary, certain mutations in 3’UTR
of mRNAs can create new potential miRNA binding sites, which can
increase the risk of uncontrolled proliferation. However, there are
several instances in which the variation in 3’UTR by mutations/SNPs is
found to be associated with reduced cancer risk.42
Apart from these complex regulations, we must remember that miRNAs are
often part of certain important gene regulatory
motifs.18,43–46 Aberrant expression of miRNAs or
their regulators affect the overall dynamical output of these motifs and
lead to various cellular fates. However, these miRNA regulatory dynamics
are highly complex and diverse. In this regard, mathematical and
computational modeling studies47,48 proved quite
insightful in describing the features of miRNA mediated gene regulation
and their pivotal role in various gene regulatory motifs. One can
envisage that studies combining quantitative experimental data along
with mathematical or computational models could even lead to better
insight into the miRNA mediated diverse gene expression responses,
especially in the context of cellular proliferation. In this review, we
gave a brief account of these kinds of theoretical and computational
studies related to specific aspects of miRNA dynamics by highlighting
the experimentally known facts about the miRNA regulations in general.
We emphasized various experimental studies that dealt with the
structural, dynamical, and concentration-dependent regulations of miRNA
concerning the proliferation of mammalian cells, and discussed the role
played by the mathematical or computational modeling in deciphering the
comprehensive mechanistic insights about miRNA regulations. Finally, we
concluded by showcasing the possible unexplored domains (such as miRNA
mediated target gene upregulation via translation activation), where
modeling studies can provide some initial insights to understand the
complex and diverse miRNA regulation, especially in the direction of
oncogenesis related issues.