Influence of circular RNA topology on microRNA stability

Abstract

AbstractCircular 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 seems critical for TDMD. Through a novel system that expresses a circRNA while reducing the co-expressed cognate linear RNA, we propose that circRNAs cannot induce TDMD. Interestingly, this appears 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 thatCdr1ascircular RNA protects miR-7 from Cyrano-mediated TDMD, we demonstrate that depletion ofCdr1asreduces miR-7 abundance, while overexpression of an artificial linear version ofCdr1asdrives TDMD. By analysing RNA sequencing data of a neuron differentiation system, we detect potential events of circRNA-mediated microRNA stabilization. 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.