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.