Influence of RNA circularity on Target RNA-Directed MicroRNA Degradation

Abstract

Circular RNAs (circRNAs) have been proposed to "sponge" or block microRNAs, a property shared with linear RNAs. Alternatively, certain RNAs induce microRNA destruction through the process of Target RNA-Directed MicroRNA Degradation (TDMD). Whether both linear and circular transcripts are equivalent in driving TDMD is unknown. Here we show that RNA topology is critical for TDMD. Through a novel system that expresses a circRNA while reducing the co-expressed cognate linear RNA, we demonstrate that circRNAs cannot induce TDMD. Interestingly, this is attributed to the circular RNA topology and not to its sequence, which is TDMD-competent in its linear form. Similarly, based on the previous knowledge that CDR1as/ciRS-7 circular RNA protects miR-7 from Cyrano-mediated TDMD, we demonstrate that depletion of CDR1as/CirS-7 reduces mir-7 levels, while overexpression of an artificial linear version of CDR1as/ciRS-7 drives TDMD. By analyzing RNA sequencing data of a neuron differentiation system, we suggest that circRNA-mediated microRNA stabilization is widespread. Our results support a model in which circRNAs, unlike linear mRNAs, lead to a topology-dependent TDMD evasion, aiding in the stabilization of specific microRNAs.