Abstract
Circular RNAs (circRNAs) represent an abundant and conserved entity of non-coding RNAs; however, the principles of biogenesis are currently not fully understood. Here, we identify two factors, splicing factor proline/glutamine rich (SFPQ) and non-POU domain-containing octamer-binding protein (NONO), to be enriched around circRNA loci. We observe a subclass of circRNAs, coined DALI circRNAs, with distal inverted Alu elements and long flanking introns to be highly deregulated upon SFPQ knockdown. Moreover, SFPQ depletion leads to increased intron retention with concomitant induction of cryptic splicing, premature transcription termination, and polyadenylation, particularly prevalent for long introns. Aberrant splicing in the upstream and downstream regions of circRNA producing exons are critical for shaping the circRNAome, and specifically, we identify missplicing in the immediate upstream region to be a conserved driver of circRNA biogenesis. Collectively, our data show that SFPQ plays an important role in maintaining intron integrity by ensuring accurate splicing of long introns, and disclose novel features governing Alu-independent circRNA production.
Highlights
Gene expression is the output of multiple tightly coupled and controlled steps within the cell, which are highly regulated by a variety of factors and processes
While proximal inverted Alu elements (IAEs) are important for the biogenesis of a subset of circular RNA (circRNA) (Jeck et al, 2013; Ivanov et al, 2015), we and others have shown that long flanking introns associate with circRNA loci, for the conserved and abundant circRNAs (Stagsted et al, 2019; Westholm et al, 2014), and the biogenesis of this group of circRNA species is largely unresolved
By RNA association and dimerization, RNA-binding proteins (RBPs) have a similar ability to juxtapose splice sites destined for backsplicing, this currently only seems to apply to a few specific cases (Conn et al, 2015; Errichelli et al, 2017; Ashwal-Fluss et al, 2014; Kramer et al, 2015)
Summary
Gene expression is the output of multiple tightly coupled and controlled steps within the cell, which are highly regulated by a variety of factors and processes Among these are the physical and functional interactions between the transcriptional and splicing machineries that are of great importance for the generation of both canonical and alternative isoforms of RNA transcripts. Exon skipping has been shown to stimulate circularization of the skipped exon (Barrett et al, 2015) In both human and Drosophila, biogenesis of the most abundant and conserved pool of circRNAs tend to be driven by long flanking introns rather than the presence of proximal inverted repeats in the flanking sequences (Westholm et al, 2014; Stagsted et al, 2019).
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