DIFFERENTIAL ROLE OF CIRCULAR AND LINE- AR TARGET RNAS ON MICRORNA STABILITY

FEDERICO FUCHS WIGHTMAN; HELGE GROSSHANS; SEBASTIÁN KADENER; LAURA MORELLI; MANUEL DE LA MATA

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Non-coding RNAs (ncRNAs) have emerged as key regu- lators of gene expression. Their functions range from scaffolds for the assembly of macromolecular complexes to catalytic activities. In neurons, which rely not only on the activity but also on the three dimensional localization of complexes, non-coding RNAs present a great potential to exert relevant functions and regulations. Circular RNAs (circRNAs) are a diverse class of ncRNAs shown to be parti- cularly abundant in neurons and, although their function/s remain/s largely unknown, some of them bind and interfere with microRNA (miRNA) activity. However, it remains unclear whether this ?miRNA sponge? effect involves mechanisms that affect activity and/or stabi- lity of miRNAs. The latter is conceivable considering that under cer- tain conditions, high af nity target RNAs can trigger miRNA degra- dation, reverting their canonical function normally leading to speci c target RNA degradation. This so-called target RNA-directed miRNA degradation (TDMD) is highly effective in neurons. Our preliminary data suggest the intriguing possibility that circRNAs binding tightly to 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 stabili- ty and activity. In particular, we are exploring the role of an abundant circRNA (ciRS7) in controlling the stability/activity of a speci c miR- NA (miR-7) that speci cally 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 patho- genesis 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.