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Understanding principles of miRNA target recognition and function through integrated biological and bioinformatics approaches

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In recent times, microRNA (miRNA) have emerged as primary regulators of fundamental biological processes including cellular differentiation, proliferation, apoptosis, as well as synaptic plasticity. However, miRNAs bind their targets with only partial complementarity, making it very challenging to determine exactly how a miRNA is functioning in specific biological environments. This review discusses key principles of miRNA target recognition and function which have emerged through the progressive advancement of biological and bioinformatics approaches. Ultimately, the integration of gene expression and biochemical methods with sequence‐ and systems‐based bioinformatics approaches will reveal profound insights regarding the importance of target contextual features in determining miRNA target recognition and regulatory outcome, as well as the importance of RNA interaction networks in enabling miRNA to regulate different target genes and functions in specific biological contexts. There is therefore a demand for the elegant design of future experiments such that principles of context‐specific miRNA target recognition and regulatory outcome can be accurately modeled in normal developmental and disease states. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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A model for canonical microRNA (miRNA) biogenesis and function in animals. After being transcribed by RNA polymerase II, pri‐miRNAs are cleaved in the nucleus by Drosha, which forms a microprocessor complex with DGCR8. This generates a pre‐miRNA, which is exported to the cytoplasm via a RanGTP/exportin 5‐dependent mechanism. In the cytoplasm, Dicer binds and cleaves the base of the pre‐miRNA stem to produce the mature miRNA duplex. This miRNA duplex is loaded into the RNA‐induced silencing complex (RISC), in which the passenger strand is discarded. The remaining miRNA strand functions to guide the mature RISC to regions of complementarity within mRNA transcripts, thereby mediating post‐transcriptional gene silencing (PTGS) through translational repression and/or mRNA degradation. It should also be noted that, whilst less common, alternative miRNA biogenesis pathways do exist. For example, mature miRNA can be generated from miRNA‐intron (mirtron) genes in which small hairpins are formed from short intronic regions and subsequently spliced into pre‐miRNA in a Drosha‐independent process.
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A schematic of microRNA (miRNA)/target competition within the RNA regulatory network. Panels (a)–(c) indicate how with increasing miRNA (blue) expression, a higher proportion of miRNA targets are regulated. However, as there is competition among miRNAs for RNA‐induced silencing complex (RISC) loading, increases in expression levels of specific miRNAs can displace other miRNAs from RISC loading, and the diversity of miRNA‐mediated regulation can subsequently be reduced. This may also result in the binding of miRNAs to target sites normally occupied by other miRNAs, as represented in panel (c) for transcript D. Panels (d–f) demonstrate how the abundance of miRNA target transcripts (red) influences the diversity of target gene regulation. These targets may represent mRNA or noncoding competitive endogenous RNA (ceRNA) transcripts, with highly expressed targets capable of ‘soaking up’ the available miRNA and thereby inhibiting the ability of the miRNA to regulate other transcripts. This characteristic of miRNA function is exploited with the transfection of ‘sponge’ expression constructs to inhibit miRNA function, and in such a way miRNAs therefore function to regulate the expression of all targets within their regulatory module, though the expression level of each transcript within this module subsequently determines which subset of targets will be regulated at a given point in time.
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Types of microRNA (miRNA) binding sites. Various thresholds of complementarity exist for miRNA‐target recognition. Canonical seed types 7mer‐A1, 7mer‐m8, and 8mer comprise the predominant types of seed sites capable of mediating target recognition through 5′‐dominant seed binding, with supplementary 3′‐base pairing also capable of increasing binding efficacy to produce 5′‐dominant canonical binding. Marginal 6mer seed sites can also facilitate miRNA binding, though 3′‐compensatory binding of ≥4–5 contiguous base pairs is often required to enhance binding efficacy. Atypical binding without seed site recognition can also occur, as has been observed for targets displaying extensive contiguous base pairing throughout the central region of the miRNA.
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RNA Evolution and Genomics > Computational Analyses of RNA
RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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