Cell-Type Specific Features of Circular RNA Expression

Abstract

Thousands of loci in the human and mouse genomes give rise to circular RNA transcripts; at many of these loci, the predominant RNA isoform is a circle. Using an improved computational approach for circular RNA identification, we found widespread circular RNA expression in Drosophila melanogaster and estimate that in humans, circular RNA may account for 1% as many molecules as poly(A) RNA. Analysis of data from the ENCODE consortium revealed that the repertoire of genes expressing circular RNA, the ratio of circular to linear transcripts for each gene, and even the pattern of splice isoforms of circular RNAs from each gene were cell-type specific. These results suggest that biogenesis of circular RNA is an integral, conserved, and regulated feature of the gene expression program.

Author Summary

Last year, we reported that circular RNA isoforms, previously thought to be very rare, are actually a pervasive feature of eukaryotic gene expression programs; indeed, the major RNA isoform from hundreds of human genes is a circle. Previous novel RNA species that initially appeared to be special cases, of dubious biological significance, have subsequently proved to have critical, conserved biological roles. An almost universal characteristic of regulatory macromolecules is that they are themselves regulated during development and differentiation. Here, we show that the repertoire of genes expressing circular RNA, the relative levels of circular: linear transcripts from each gene, and even the pattern of splice isoforms of circular RNAs from each gene were cell-type specific, including examples of striking regulation. In humans, we estimate that circular RNA may account for about 1% as many molecules as poly(A) RNA. The ubiquity of circular RNA and its specific regulation could significantly alter our perspective on post-transcriptional regulation and the roles that RNA can play in the cell.