A network of noncoding regulatory RNAs acts in the mammalian brain III

Noncoding RNAs (ncRNAs) play increasingly appreciated gene-regulatory roles. Here, we describe a regulatory network centered on four ncRNAs—a long ncRNA, a circular RNA, and two microRNAs—using gene editing in mice to probe the molecular consequences of disrupting key components of this network. The long ncRNA Cyrano uses an extensively paired site to miR-7 to trigger destruction of this microRNA. Cyrano-directed miR-7 degradation is much more efficient than previously described examples of target-directed microRNA degradation, which come from studies of artificial and viral RNAs. By reducing miR-7 levels, Cyrano prevents repression of miR-7–targeted mRNAs and enables the accumulation of Cdr1as, a circular RNA known to regulate neuronal activity. Without Cyrano, excess miR-7 causes cytoplasmic destruction of Cdr1as, in part through enhanced slicing of Cdr1as by a second miRNA, miR-671. Thus, several types of ncRNAs can collaborate to establish a sophisticated regulatory network. miRNA expression profiling by small-RNA sequencing of cerebellum and hippocampus from wild-type (WT) and Cyrano–/– (CyrKO) mice, and of cerebellum from Cdr1as miR-671 site mutant (Cdr1as671), and double mutant (CyrKO;Cdr1as671) mice. This study consists of 18 libraries generated from 3 biological replicates per genotype for each tissue.