Li, Z., Xu, B., Wang, Z., Zhang, W., Fu, J., Wu, L., Bao, N., Xie, J., Yan, R., Dong, H., Jin, Y. (2025). A single Drosophila Dscam1 genomic locus generates a vast repertoire of circRNAs facilitated by RNA pairing.  Insect Biochem. Mol. Biol. 185(): 104423.

FBrf0263823

Research paper

Drosophila melanogaster Dscam1 gene has the potential to generate 38,016 linear isoforms through mutually exclusive alternative splicing. Here, using a tailored approach, we identified thousands of circRNA isoforms derived from the Dscam1 locus, representing the highest number of circRNA isoforms produced by a single gene to date. The extensive organization of alternative circularization of Dscam1s is conserved within Insecta. Notably, the analysis of circRNA isoforms revealed that alternative back-splicing of variable exon 4s and 6s occurs in a proximity-dependent manner. Interestingly, unlike the classical "loop-in" model mediated by RNA pairing between flanking introns, we revealed a "loop-out" mechanism, in which RNA secondary structures between docking sites and selector sequences facilitate the back-splicing of exons located outside the loop. These findings expand the understanding of the mechanism underlying the generation of circRNA and provide new insights into the expression regulation of highly complex gene loci.