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Mirtrons, an emerging class of atypical miRNA

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Post‐transcriptional gene silencing (PTGS) via RNA interference (RNAi) is a vital gene regulatory mechanism for fine‐tuning gene expression. RNAi effectors termed microRNAs (miRNAs) are implicated in various aspects of animal development and normal physiological function, while dysregulation has been linked to several pathologies. Several atypical miRNA biogenesis pathways have been identified, yet in most cases the reasons for their emergence remain unclear. One of these atypical pathways is the mirtron pathway, where short introns are excised by splicing to generate intermediates of the RNAi pathway, with no cleavage by the microprocessor. Closely related pathways involving tailed‐mirtron and simtron biogenesis have also been described. There is extensive evidence that mirtrons function as miRNAs, and while some are evolutionarily conserved across similar species, others appear to have emerged relatively recently. In addition, through exploitation of the potent and sequence‐specific silencing capabilities of RNAi, synthetic mirtrons may have potential for overcoming certain therapeutic challenges. WIREs RNA 2012 doi: 10.1002/wrna.1122

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Figure 1.

Canonical miRNA and mirtron pathways. (a) In the canonical mammalian miRNA pathway, pri‐miRNA transcripts are processed by the microprocessor complex (Drosha/DGCR8) into pre‐miRNA hairpins that are recognized by Exportin‐5 for nuclear export. Further processing by Dicer, recruitment into RISC, and strand selection result in a mature antisense species capable of directing translational repression of imperfectly matched targets or target cleavage of perfectly matched targets. (b) In the mirtron pathway, pre‐miRNA hairpins are produced directly from introns via splicing of pre‐mRNAs, whereby functional mature mRNAs are also produced. The hairpins are then thought to join the canonical pathway at the stage of nuclear export, not requiring any processing by Drosha. (c) Tailed mirtrons derive from slightly larger introns, and are spliced from pre‐mRNA, but a single tail remains on one strand (here the 5′ strand), which is digested by an exonuclease. Again these hairpins then join the canonical pathway for nuclear export.

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Figure 2.

Atypical biogenesis pathways for miRNA generation. (a) The mirtron pathway involves splicing of short introns with hairpin‐forming potential. Following debranching of the branched lariat intermediate of the splicing pathway, sequence homology between 5′ and 3′ ends of the intron allows pre‐miRNA‐like hairpins to form. (b, c) Tailed mirtrons are very similar to mirtrons, arising from short introns with hairpin‐forming potential. However, following debranching, the pre‐miRNA‐like hairpin has a single‐stranded tail on either the 5′ or 3′ end which requires exonucleolytic cleavage by a Drosha‐independent mechanism. (d) miR‐320 and miR‐484 are pri‐miRNA sequences devoid of Drosha recognition characteristics. Dicer processes the hairpins directly to release mature miRNAs. (e) Some miRNA map to snoRNAs containing secondary structures mimicking Dicer substrates. Following initial processing by a Drosha‐independent mechanism, hairpin structures are processed by Dicer into mature miRNAs. (f) tRNA‐like secondary structures can be processed by Dicer to release short RNA species from their 3′ ends in mammals. (g) miRNAs encoded by the MHV68 virus derive from complex secondary structures incorporating pol‐III promoters and which are analogous to tRNAs. In initial processing tRNAaseZ cleave to release a hairpin sequence that is recognized by Dicer. (h) Endogenous siRNAs can derive from long inverted repeat sequences that are cleaved by a homolog of Dicer in Drosophila to shorter hairpins recognized by Dicer. Alternatively, mRNA transcripts can anneal to complementary antisense transcripts and form dsRNA duplexes that are recognized and processed by Dicer. A number of pathways are also known which are independent of Dicer. (i) Some mirtron‐like miRNAs may be processed via the simtron route, requiring Drosha but not splicing, DGCR8, or Dicer. (j) Pri‐miR‐451 is processed by Drosha into a hairpin shorter than canonical Dicer substrates, and the mature miRNA enters the hairpin loop. AGO2 has been found to mediate processing of the pre‐miRNA into the mature sequence. (k) In addition to Dicer‐dependent cleavage of tRNAs, tRNAseZ can also cleave 3′ sequences of precursor tRNAs to release small RNAs that can enter gene‐silencing pathways.

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Figure 3.

Examples of canonical miRNAs, mirtrons, and tailed mirtrons from Drosophila melanogaster. (a) let‐7, a canonical miRNA. The primary transcript contains an extended hairpin which is first cleaved by Drosha to produce the pre‐miRNA. The loop region is then removed by Dicer and the mature miRNA strand is incorporated into RISC. (b) miR‐1003, a mirtron: a miRNA produced from an intron without Drosha cleavage. The primary transcript is spliced, forming a functional mRNA and a pre‐miRNA hairpin which is cleaved by Dicer as in (a). (c) miR‐1017, a tailed mirtron. The primary transcript is spliced as in (b), except that the pre‐miRNA hairpin produced contains a tail of around 100 nucleotides on the 3′ arm. This is digested by a 3′‐5′ exonuclease (the RNA exosome in Drosophila).19

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Figure 4.

Gene therapy strategies for dominant toxic gain‐of‐function conditions. In this representation of a dominant condition, in the disease state (top) the mutant (red) protein forms aggregates which also incorporate the wild‐type (green) protein. (a) Allele‐specific silencing, where possible, reduces levels of mutant protein only, to prevent aggregation while leaving expression of the wild‐type allele unaffected. (b) Non‐allele‐specific silencing may effectively reduce aggregation but lead to deficiency, which may cause known or unknown deleterious effects. (c) Knockdown and replacement add functional protein alongside non‐allele‐specific knockdown to avoid deficiency.

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Figure 5.

Potential strategies for gene knockdown‐replacement (K&R) therapy. (a) Delivery of a targeting siRNA molecule and a transcriptional unit encoding a pol‐II/III driven replacement gene.81,84 (b) Delivery of two transcriptional units: a constitutive pol‐III driven shRNA and pol‐II/III driven replacement gene.83,85,86 (c) Delivery of a single construct containing two separate pol‐II transcription units: one produces a miRNA mimic and the other produces the replacement gene. (d) A single transcriptional unit driven by a single pol‐II promoter where an intronic miRNA mimic is expressed from inside the replacement gene and the transcript is processed by Drosha and splicing.82 (e) As (d), with a mirtron mimic as a special case of intronic miRNA, which does not require Drosha processing.

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