Circular RNA Is Expressed across the Eukaryotic Tree of Life

Abstract

An unexpectedly large fraction of genes in metazoans (human, mouse, zebrafish, worm, fruit fly) express high levels of circularized RNAs containing canonical exons. Here we report that circular RNA isoforms are found in diverse species whose most recent common ancestor existed more than one billion years ago: fungi (Schizosaccharomyces pombe and Saccharomyces cerevisiae), a plant (Arabidopsis thaliana), and protists (Plasmodium falciparum and Dictyostelium discoideum). For all species studied to date, including those in this report, only a small fraction of the theoretically possible circular RNA isoforms from a given gene are actually observed. Unlike metazoans, Arabidopsis, D. discoideum, P. falciparum, S. cerevisiae, and S. pombe have very short introns (∼100 nucleotides or shorter), yet they still produce circular RNAs. A minority of genes in S. pombe and P. falciparum have documented examples of canonical alternative splicing, making it unlikely that all circular RNAs are by-products of alternative splicing or ‘piggyback’ on signals used in alternative RNA processing. In S. pombe, the relative abundance of circular to linear transcript isoforms changed in a gene-specific pattern during nitrogen starvation. Circular RNA may be an ancient, conserved feature of eukaryotic gene expression programs.

Circular RNAs: Unexpected outputs of many protein-coding genes

“…87 It has additionally been proposed that many Drosophila circular RNAs are generated independently of repeats. 29 This suggests the existence of alternative mechanisms for circular RNA biogenesis.…”

Repetitive elements regulate circular RNA biogenesis

“…49 In addition, various noncoding RNAs in archaea are processed to yield circular RNAs through poorly understood mechanisms. 50 In summary, thousands of protein-coding genes generate circular RNAs 13,[28][29][30][31][32] and we are beginning to understand the key elements that facilitate their biogenesis. Both computational analyses and plasmid-based experiments have pointed to a key role for base pairing between intronic complementary sequences in promoting most backsplicing events.…”

Circular RNAs: New Players in Gene Regulation

“…Due to their closed loop form, they cannot be mapped directly to the genome, which is probably one of the reasons for the late discovery of these relatively new RNA species. They appear to be ancient, conserved regulators of eukaryotic gene expression [9] and were initially detected in ribosomal depleted RNA-seq data [2]. Due to the lack of free ends circRNAs are resistant to exonucleases and have reduced rates of turnover [10].…”

“…Evidence for expression of circRNA was found in Drosophila [6] [12] where over 2500 circRNAs were annotated [14]. Several studies showed that different circRNA structures can be produced by alternative splicing from the same gene [9] [12], and this feature adds considerably to their diversity.…”