Unannotated splicing regulatory elements in deep intron space

Abstract

Deep intron space harbors a diverse array of splicing regulatory elements that cooperate with better-known exon-proximal elements to enforce proper tissue-specific and development-specific pre-mRNA processing. Many deep intron elements have been highly conserved through vertebrate evolution, yet remain poorly annotated in the human genome. Recursive splicing exons (RS-exons) and intraexons promote noncanonical, multistep resplicing pathways in long introns, involving transient intermediate structures that are greatly underrepresented in RNA-seq datasets. Decoy splice sites and decoy exons act at a distance to inhibit splicing catalysis at annotated splice sites, with functional consequences such as exon skipping and intron retention. RNA:RNA bridges can juxtapose distant sequences within or across introns to activate deep intron splicing enhancers and silencers, to loop out exons to be skipped, or to select one member of a mutually exclusive set of exons. Similarly, protein bridges mediated by interactions among transcript-bound RNA binding proteins (RBPs) can modulate splicing outcomes. Experimental disruption of deep intron elements serving any of these functions can abrogate normal splicing, strongly suggesting that natural mutations of deep intron elements can do likewise to cause human disease. Understanding noncanonical splicing pathways and discovering deep intron regulatory signals, many of which map hundreds to many thousands of nucleotides from annotated splice junctions, is of great academic interest for basic scientists studying alternative splicing mechanisms. Hopefully, this knowledge coupled with increased analysis of deep intron sequences will also have important medical applications, as better interpretation of deep intron mutations may reveal new disease mechanisms and suggest new therapies. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing.

Keywords: RNA bridge; alternative splicing; deep intron regulatory elements; intrasplicing; recursive splicing.