Embryonic circular RNAs at tandem duplicated genes in zebrafish present new paradigm in gene expression

Abstract

Circular RNAs are a puzzling class of RNAs with covalently closed loop structure, lacking 5 and 3 ends. Present in all cells, no unifying theme has emerged regarding their function. Here, we use transcriptional data obtained by biotagging in zebrafish to uncover a high-resolution cohort of embryonic circRNAs expressed in nuclear and polysomal subcellular compartments in three developmental cell types. The ample presence of embryonic circRNAs on polysomes contradicts previous reports suggesting predominant nuclear localisation. We uncover a novel class of circRNAs, significantly enriched at tandem duplicated genes. Using newly-developed NGS-based approach, we simultaneously resolve the full sequence of putative \"tandem-circRNAs\" and their underlying mRNAs. These form by long-range cis-splicing events often between distant tandem duplicated genes, resulting in chimaeric mRNA transcripts and circRNAs containing their supernumerary excised exons, integrated from multiple tandem loci. Taken together, our results suggest that circularisation events rather than circRNAs themselves are functionally important.