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Unannotated splicing regulatory elements in deep intron space

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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
Recursive splicing. Model transcript with two constitutive exons in black (E1, E2) separated by a long intron containing two RS ratchet points associated with two RS‐exons in gray. The major successive recursive splicing events are indicated by the dotted lines and numbered from (1) to (3). Minor splicing pathways shown by light gray dotted lines can, in some genes, include the RS‐exon
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RBP bridging interactions in the TCF3 gene. A conserved splicing silencer element in the intron binds PTBP1. It is recruited to block splicing of either exon 18a, by unknown interactions, or exon 18b, by interaction with HNRNPH1 (Yamazaki et al., 2019)
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RNA bridging interactions activate a distal splicing enhancer. Three RBFOX motifs approximately 1.8 kb downstream of ENAH alternative exon 11 can enhance splicing of the exon in an RNA bridge‐dependent manner (Lovci et al., 2013)
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Docking/selector mechanism for splicing of mutually exclusive exons. Model transcript representing a simplified version of the Dscam exon 6 cluster showing 5 mutually exclusive exons rather than the full complement of 48 variants. The selected exon 6 variant, marked by asterisks, is recruited close to exon 5 by the docking–selector interaction. Splicing to exon 5 activates it for subsequent splicing to exon 7
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Decoy exon in the human SF3B1 gene. Thick red line indicates a retained intron. Of the six candidate decoy exons in intron 4, only the strongest (exon 4e) is depicted. In a splice‐site dependent manner, it blocks splicing at the ends of the intron as indicated by the red arrows
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Intrasplicing in the human EPB41 gene. Upper panel: Two steps of intrasplicing for transcripts initiated at exon 1A, numbered (1) and (2). Splice site elements for first nested splice are in gray; splice elements for second nested splice are in black. Lower panel: Transcripts initiated downstream of the intraexon at exon 1C splice directly in one step to the first AG dinucleotide in exon 2′. iE, intraexon; bp1 and bp2, branchpoints used in the two steps of intrasplicing
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