DIFFERENTIAL ROLE OF CIRCULAR AND LINEAR TARGET RNAS ON MICRORNA STABILITY.

FUCHS, F.; GROSSHANS, H.; KADENER, S.; MORELLI, L.; DE LA MATA, M.

Congreso; Reunion de Sociedades Conjuntas; 2017

Non-coding RNAs (ncRNAs) have emerged as key regulatorsof gene expression. Their functions range from scaffolds forthe assembly of macromolecular complexes to catalytic activities.In neurons, which rely not only on the activity but also on the threedimensional localization of complexes, non-coding RNAs present agreat potential to exert relevant functions and regulations. CircularRNAs (circRNAs) are a diverse class of ncRNAs shown to be particularlyabundant in neurons and, although their function/s remain/slargely unknown, some of them bind and interfere with microRNA(miRNA) activity. However, it remains unclear whether this ?miRNAsponge? effect involves mechanisms that affect activity and/or stabilityof miRNAs. The latter is conceivable considering that under certainconditions, high affinity target RNAs can trigger miRNA degradation,reverting their canonical function normally leading to specifictarget RNA degradation. This so-called target RNA-directed miRNAdegradation (TDMD) is highly effective in neurons. Our preliminarydata suggest the intriguing possibility that circRNAs binding tightlyto miRNAs might bypass TDMD and stabilize miRNAs, as opposed to linear targets which trigger TDMD leading to miRNA degradation. Through bioinformatic predictions and experimental approaches we aim at characterizing how circular RNA species affect miRNA stability and activity. In particular, we are exploring the role of an abundant circRNA (ciRS7) in controlling the stability/activity of a specific miRNA (miR-7) that specifically binds to it and which was shown to be downregulated in sporadic Alzheimer?s disease (AD). Because miR-7 has several predicted targets of central importance to the pathogenesis of AD, understanding the consequences of miR-7 stability changes upon ciRS7 level variations will increase our knowledge of both circRNA funtions and the biological mechanisms of AD.