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UK Team Links Sense Strand 'Mirror microRNA' in Mammalian Cells to Neuronal Function

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Opening the door to the possibility of a new class of small, non-coding RNA, a team of researchers from the UK reported last month that they have identified in mammalian cells a fully processed and functional microRNA that is produced from the sense strand of DNA.

Dubbed miR-3120, this so-called mirror miRNA was located in neuronal cell bodies and targets heat shock cognate protein 70 and auxilin expression, according to a paper in the Journal of Biological Chemistry. Lentiviral-mediated expression of the mirror miRNA, meantime, was shown to inhibit the uncoating of clathrin-coated vesicles, suggesting a role in the regulation of neuronal pathways associated with synaptic vesicle function and neuronal plasticity

"We have now found that both sides of the double helix can each produce a microRNA,” University of Bristol researchers Helen Scott and Joanna Howarth, who were the lead authors of the study, said in a statement.

“These two microRNAs are almost a perfect mirror of each other, but due to slight differences in their sequence, they regulate different sets of protein-producing RNAs, which will in turn affect different biological functions,” they added. “Such mirror microRNAs are likely to represent a new group of microRNAs with complex roles in coordinating gene expression, doubling the capacity of regulation."

Although both sense and antisense miRNA hairpin structures have been shown to form from Drosophila genes, mirror miRNAs were previously only predicted to exist in mammals, according to the JBC paper.

Working with colleagues from the University of Manchester and the Cyprus Institute of Neurology and Genetics, however, the University of Bristol team was able to show that a single locus within intron 13 of the dynamin-3 gene encodes two mirror miRNAs, miR-3120 and miR-214.

The first is produced following transcription and mRNA processing, while the second is produced by antisense transcription, they wrote. Notably, “miR-3120 was also shown to be fully processed to a functional miRNA and to be expressed with miR-214 and its host gene dynamin-3 in neurons.

“Many similar examples of mammalian mirror or complementary miRNAs could exist,” they stated in JCB. “However, this is the first example characterized in mammals, suggesting that it is rare for both miRNAs to have sustained beneficial effects allowing them to be retained by natural selection.”

The mirror miRNA was found to target the clathrin-uncoating enzyme Hsc70, as well as its co-chaperone auxilin. When miR-3120 was down-regulated in vitro, the researchers observed a significant uptick in expression of Hsc70, which they said demonstrates the miRNA's role in regulating constitutive levels of the enzyme.

“Interestingly, the miR-312 binding sites were … found to exist within defined 3′-UTR AU-rich elements (ARE) motifs that were themselves conserved between human and rat,” they noted. “The co-localization of miR-3120 binding sites within conserved ARE-binding regions suggests that a novel mechanism for the control of Hsc70 translation and rapid changes in Hsc70 translation are needed to regulate its physiological functions,” which include the folding and translocation of polypeptides and the activation of the glucocorticoid receptor in combination with other chaperones.

“Our observations showing that the miR-3120 inhibits clathrin-mediated uncoating are in agreement with previous studies of Hsc70 and auxilin function,” the investigators wrote. “Importantly, they also show that miRNAs mediate a previously unknown level of control over the processes governing endosomal trafficking. It is also interesting to note that the miR-3120 host gene, dynamin-3, associates with clathrin and mediates the rapid reformation of synaptic vesicles after endocytosis.”

Further, the disruption of dynamin-3 function results in “reduced synaptic vesicle recycling and altered synaptic transmission,” they added.

Because miR-3120 regulates vesicle uncoating and miR-214 is known to target PTEN, which interacts with dynamin and regulates synaptic proteins involved in receptor cycling and synaptic plasticity, the two miRNAs “may represent a novel genetic unit that has evolved to regulate the complex neuronal pathways associated with synaptic vesicle function and neuronal plasticity,” they concluded.

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