Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Abstract

The ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth. Current knowledge on functional RNA structures is focused on locally-occurring base pairs. However, crosslinking and proximity ligation experiments demonstrated that long-range RNA structures are highly abundant. Here, we present the most complete to-date catalog of conserved complementary regions (PCCRs) in human protein-coding genes. PCCRs tend to occur within introns, suppress intervening exons, and obstruct cryptic and inactive splice sites. Double-stranded structure of PCCRs is supported by decreased icSHAPE nucleotide accessibility, high abundance of RNA editing sites, and frequent occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNAPII slowdown suggesting that splicing is widely affected by co-transcriptional RNA folding. The enrichment of 3’-ends within PCCRs raises the intriguing hypothesis that coupling between RNA folding and splicing could mediate co-transcriptional suppression of premature pre-mRNA cleavage and polyadenylation.

Hidden RNA pairings counteract the “first-come, first-served” splicing principle to drive stochastic choice in Dscam1 splice variants

“…S14 and S15). Analogous nested RNA secondary structures have been found in the catalog of pairs of conserved complementary regions (PCCRs) in human protein-coding genes ( 47 ). Likewise, two groups of RNA structural modules have been shown to operate together to dynamically regulate alternative splicing in the human Ate1 gene ( 48 ).…”

Secondary structures in RNA synthesis, splicing and translation

“…Long range interactions are important for splicing modulation [141] , and they are more enriched at weak alternative acceptor splice sites [142] . Some long range interactions can span several kilobases and can bring in proximity otherwise distant splice sites.…”

Tandem Exon Duplications Expanding the Alternative Splicing Repertoire

“…This model implies that the mutually exclusive splicing pattern is an inevitable consequence of tandem exon duplications. Considering the high abundance of conserved complementary regions in the UTRs of human genes [ 45 ], it appears plausible that tandem exon duplications within UTRs also could generate competing RNA structures leading to mutually exclusive exon inclusion.…”