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Mutually exclusive alternative splicing of pre‐mRNAs

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Pre‐mRNA alternative splicing is an important mechanism used to expand protein diversity in higher eukaryotes, and mutually exclusive splicing is a specific type of alternative splicing in which only one of the exons in a cluster is included in functional transcripts. The most extraordinary example of this is the Drosophila melanogaster Down’s syndrome cell adhesion molecule gene (Dscam), which potentially encodes 38,016 different isoforms through mutually exclusive splicing. Mutually exclusive splicing is a unique and challenging model that can be used to elucidate the evolution, regulatory mechanism, and function of alternative splicing. The use of new approaches has not only greatly expanded the mutually exclusive exome, but has also enabled the systematic analyses of single‐cell alternative splicing during development. Furthermore, the identification of long‐range RNA secondary structures provides a mechanistic framework for the regulation of mutually exclusive splicing (i.e., Dscam splicing). This article reviews recent insights into the identification, underlying mechanism, and roles of mutually exclusive splicing. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
Examples of genes containing complex mutually exclusive exon (MXE) clusters. Constitutive exons (in black boxes), alternative exons (in colored boxes), and introns (lines) are shown. The exons in each alternatively spliced cluster are shaded in a different color. Dotted lines represent alternative splicing events. The number of exons in each alternatively spliced cluster is annotated below the cluster. The total number of potential isoforms is indicated on the right. Genomic organizations containing MXEs have been described in Drosophila melanogaster Dscam (Schmucker et al., ), D. melanogaster Mhc (Bernstein, Mogami, Donady, & Emerson, ), D. melanogaster multidrug resistance‐associated protein 1 (MRP1) (Grailles, Brey, & Roth, ), Manduca sexta Spn4 (Jiang et al., ), Branchiostoma floridae MRP (Yue et al., ), and human CD55 (Hatje et al., )
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Different models of alternative splicing events. Constitutive exons (black boxes), alternative exons (colored boxes), introns (lines), and splice junctions (dotted lines) are shown. Exon skipping (a), intron retention (b), alternative donor and acceptor splice sites (c, d), mutually exclusive splicing (e), and pairwise mutually exclusive splicing (f)
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Mutually exclusive splicing acts as a regulatory switch. (a) A mutually exclusive splicing switch in regulating pluripotency and reprogramming (Gabut et al., ). Two isoforms, Foxp1 and Foxp1‐ES, are generated via mutually exclusive splicing. In embryonic stem cells (ESCs), exon 18b inclusion results in the expression of FOXP1‐ES, which promotes pluripotency genes while simultaneously repressing differentiation‐associated genes. In differentiated cells, exon 18 inclusion leads to the production of FOXP1, thereby activating the expression of differentiation‐associated genes. (b) Temperature‐dependent mutually exclusive splicing switch in flowering plants (Posé et al., ). Two FLM splice variants are regulated in an antagonistic manner by competing with the floral repressor SVP for complex formation. The formation of the SVP–FLM‐β complex predominantly occurs at low temperatures and actively inhibits precocious flowering. When the temperature increases, the SVP–FLM‐δ complex dominates and promotes flowering. The temperature‐dependent splicing regulation of FLM allows the plant to quickly sense and respond to changes in ambient temperature, ensuring the switch between the nonflowering and flowering phases of development
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Origin and evolution of mutually exclusive exons (MXEs) in bilaterian multidrug resistance‐associated proteins (MRPs). (a) Conservation and divergence of MXEs (Yue et al., ). The introns are shown as lines, and MXEs are shown in different colors, based on the various sizes of duplicated exons. The introns are not drawn to scale. MXEs of the same color are homologous. The lost MXEs are shown in a dashed box. “( )” represents the number of MXEs. MXEs may have arisen before the split of the bilaterians over 600 million years ago. The independent emergence of MXEs is depicted by different solid squares. (b) Phylogenetic analysis of MXEs, indicating independent origins of MXEs in Branchiostoma, nematodes, and insects
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Model of the control of mutually exclusive splicing by competing RNA pairings. (a) Unidirectional pairing model (Graveley, 2005; Yang et al., ). As an example, when the IE1 pairs with the docking site (Dd), such an inter‐intronic RNA pairing interaction functions to activate the splicing of exon B1 to the constitutive exon C. The remaining exons may be repressed by RNA pairing in combination with other players such as weak splice sites (red circle) and splicing repressors (red oval). Likewise, when the IE2 pairs with the Dd, exon B2 is selected. The green ovals represent splicing activators. Either way, exons B1 and B2 cannot both be included in mature mRNA at the same time. (b) Bidirectional pairing model (Yue et al., ). For an alternative exon B to be included, either docking site must alternately interact with its selector sequence. For example, when the Us pairs with the downstream Dd, such an RNA pairing functions to activate the splicing of exon 4.1 to the constitutive exon C. When the upstream docking site (Ud) pairs with the downstream selector sequence (Ds), exon 4.2 is included
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Mechanistic models underlying mutually exclusive splicing. (a) Steric interference. Steric hindrance may be caused by short distances between two splice sites of an intervening intron between two mutually exclusive exons (MXEs) (i), short distances between the 5′ splice site and the branch point (ii), or RNA secondary structures (iii). MXEs are shown in red and green, constitutive exons in blue. These mechanisms can operate in mammalian alpha‐tropomyosin (Smith & Nadal‐Ginard, ), C. elegans 14‐3‐3ξ (Yang et al., ), and insect Dscam exon 17 (Yue et al., ). (b) Spliceosomal incompatibility. This model involves a specific arrangement of splice sites that are flanked by U2‐ and U12‐type introns on either side of the exons. This model may be applicable to human stress‐activated protein kinase genes (Hatje et al., ; Letunic et al., ). (c) Nonsense‐mediated mRNA decay (NMD). This can occur if the lengths of both MXEs are not multiples of 3 nt. In this case, the altered reading frame and consequent introduction of premature stop codons can trigger the disposal of aberrantly spliced mRNAs by the NMD (Jones et al., ). NMD tends to function in combination with other mechanisms (Smith, ). (d) Competing RNA secondary structures. Competing RNA secondary structures between the docking site and selector sequences serve to guarantee that only one exon variant is included by the spliceosome. In contrast to the exon 6 cluster of Dscam, the docking sites are located in the introns downstream of the exon cluster in these genes (ii), and both docking sites are located in the upstream and downstream introns (iii). These structural codes have been observed in a considerable fraction of exon clusters, such as in Drosophila Dscam (Anastassiou et al., ; Graveley, ; Yang et al., ; Yue et al., 2016), 14‐3‐3ξ (Yang et al., 2011), srp, RIC‐3 (Yue et al., ), and multidrug resistance‐associated protein 1 (MRP1), Branchiostoma MRP (Yue et al., ), and human dynamin 1 (Suyama, ) and CD55 (Hatje et al., )
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Single‐cell alternative splicing dynamics during neuronal differentiation (Song et al., 2017). (a) Categorization of single‐cell distribution of isoforms. At single‐cell resolution, three main categories of modalities have been identified: unimodal in which most cells contain either isoform, unimodal with exon a or b inclusion, and bimodal. (b) Transformation of splicing distributions. During cell differentiation, unimodal events are largely static, whereas highly variable events are dynamic
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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Processing > Splicing Regulation/Alternative Splicing

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