Role of pri-miRNA tertiary structure in miR-17~92 miRNA biogenesis

Abstract

MicroRNAs (miRNAs) regulate gene expression in a variety of biological pathways such as development and tumourigenesis.  miRNAs  are initially expressed as long primary transcripts (pri-miRNAs) that undergo sequential processing by Drosha and then Dicer to yield mature miRNAs.  miR-17~92 is a miRNA cluster that encodes 6 miRNAs and while it is essential for development it also has reported oncogenic activity.  To date, the role of RNA structure in miRNA biogenesis has only been considered in terms of the secondary structural elements required for processing of pri-miRNAs by Drosha.  Here we report that the miR-17~92 cluster has a compact globular tertiary structure where miRNAs internalized within the core of the folded structure are processed less efficiently than miRNAs on the surface of the structure.  Increased miR-92 expression resulting from disruption of the compact miR-17~92 structure results in increased repression of integrin α5 mRNA, a known target of miR-92a.  In summary, we describe the first example of pri-miRNA structure modulating differential expression of constituent miRNAs.