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miRNA sponges: soaking up miRNAs for regulation of gene expression

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MicroRNAs (miRNAs) are small regulatory RNAs that act in an entangled web of interactions with target mRNAs to shape the cellular protein landscape by post‐transcriptional control of mRNA decay and translation. miRNAs are themselves subject to numerous regulatory mechanisms that adjust their prevalence and activity. Emerging evidence suggests that miRNAs are themselves targeted by regulatory RNA species, and the identification of several classes of noncoding RNA molecules carrying miRNA binding sites has added a new intricate dimension to miRNA regulation. Such miRNA ‘sponges’ bind miRNAs and competitively sequester them from their natural targets. Endogenous miRNA sponges, also termed competing endogenous RNAs (ceRNAs), act to buffer the activity of miRNAs on physiologically relevant targets. This class of sponges includes endogenously transcribed pseudogenes, long noncoding RNAs, and recently discovered circular RNAs and may act in large complex networks in conjunction with miRNAs to regulate the output of protein. With the growing demand of regulating miRNA activity for experimental purposes and potential future clinical use, naturally occurring miRNA sponges are providing inspiration for engineering of gene vector‐encoded sponges as potent inhibitors of miRNA activity. Combined with potent and versatile vector technologies, expression of custom‐designed sponges provides new means of managing miRNAs and soaking up miRNAs for therapeutic regulation of gene expression. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Methods > RNA Analyses in Cells

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Regulation of miRNA function. A schematic overview of regulation of miRNA activity at different stages from miRNA transcription and processing to RISC incorporation and target recognition. Different regulatory mechanisms are highlighted in yellow boxes. TF, Transcription factor; Me, Methyl group; Ac, Acetyl group; Exp‐5, Exportin 5; U, Uridine; RBP, RNA‐binding protein; RISC, RNA‐induced silencing complex.
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Engineered sponges for soaking up miRNAs. (a) A schematic representation of two vector‐encoded sponge transcripts generated by transcription from an RNA Pol II and RNA Pol III promoter, respectively. The RNA Pol II‐driven sponge contains a 5′ cap and a 3′ poly(A) tail. The miRNA target sites are usually placed within the 3′ UTR following an open reading frame (ORF), for example encoding a reporter protein. The RNA Pol III‐transcribed sponge contains only the miRNA target sites and a 2–4 uridine extension at the 3′ end. (b) Schematic depiction of a linear sponge, a Tough Decoy sponge, and a suggested design combining the optimal features from a circular RNA transcript with the configuration of a Tough Decoy sponge. (c) A depiction of a RISC‐loaded miRNA bound to a target site of a sponge. The base pairing of the miRNA is complete, but the target site is engineered to carry a central bulge to evade fast Ago2‐catalyzed cleavage and thereby prolong miRNA sequestration.
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Modulation of miRNA‐directed gene regulation by competing endogenous RNAs (ceRNAs). The figure illustrates the different species of ceRNAs that serve as miRNA pseudotargets by binding and sequestering miRNAs that would otherwise regulate a physiological relevant target (authentic target). At a high concentration of pseudotargets (low mRNA target:ceRNA ratio), the miRNA is sequestered and the authentic target is derepressed with a consequent high‐protein output. At a low concentration of pseudotargets (high mRNA target:ceRNA ratio), the miRNA is available to suppress the authentic target.
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RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
RNA Methods > RNA Analyses in Cells
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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