Long-range RNA pairings contribute to mutually exclusive splicing

Yue, Yuan; Yang, Yun; Dai, Lanzhi; Cao, Guang; Chen, Ran; Hong, Weiling; Liu, Baoping; Shi, Yang; Meng, Yijun; Shi, Feng; Xiao, Mu; Jin, Yongfeng

doi:10.1261/rna.053314.115

Cited by 27 publications

(56 citation statements)

References 47 publications

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“…Very recently, we revealed unusual RNA architecture within the exon cluster of srp (Yue et al, ). In this case, four highly conserved intronic elements were arranged as follows: one in the intron downstream from exon 3, two between exon 4.1 and exon 4.2, and one upstream of exon 5.…”

Section: Different Mechanisms Underlying Mutually Exclusive Splicingmentioning

confidence: 95%

“…Genomic organizations containing MXEs have been described in Drosophila melanogaster Dscam (Schmucker et al, 2000), D. melanogaster Mhc (Bernstein, Mogami, Donady, & Emerson, 1983), D. melanogaster multidrug resistance-associated protein 1 (MRP1) (Grailles, Brey, & Roth, 2003), Manduca sexta Spn4 (Jiang et al, 1996), Branchiostoma floridae MRP (Yue et al, 2017), and human CD55 (Hatje et al, 2017) single-cell RNA-sequencing (RNA-seq) data (Song et al, 2017). Recently, we and other researchers have indicated that the formation of long-range RNA secondary structures is involved in mutually exclusive splicing (Anastassiou, Liu, & Varadan, 2006;Graveley, 2005;May, Olson, McManus, & Graveley, 2011;Yang et al, 2011;Yue et al, 2016Yue et al, , 2017. These new discoveries range from the genome-wide identification of mutually exclusive splicing events to the elucidation of both mechanism and function.…”

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confidence: 99%

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Mutually exclusive alternative splicing of pre‐mRNAs

et al. 2018

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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.

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Section: Different Mechanisms Underlying Mutually Exclusive Splicingmentioning

confidence: 95%

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confidence: 99%

Mutually exclusive alternative splicing of pre‐mRNAs

et al. 2018

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“…Although recent studies suggested that biased isoform expression may be combinatorially regulated by the strength of base pairing between the docking site and selector sequence, the strength of the splice sites, and RNA binding proteins 23,24,25,26,27,28 , the physiological significance of the highly specific bias in isoform expression remains entirely unclear.…”

Section: Introductionmentioning

confidence: 99%

Intron-targeted mutagenesis reveals roles forDscam1RNA pairing-mediated splicing bias in neuronal wiring

Hong

Dong

Zhang

et al. 2019

Preprint

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Drosophila melanogaster Down syndrome cell adhesion molecule (Dscam1) can potentially generate 38,016 different isoforms through stochastic, yet highly biased, alternative splicing.Genetic studies demonstrated that stochastic expression of multiple Dscam1 isoforms provides each neuron with a unique identity for self/non-self-discrimination. However, due to technical obstacles, the functional significance of the highly specific bias in isoform expression remains entirely unknown. Here, we provide conclusive evidence that Dscam1 splicing bias is required for precise mushroom body (MB) axonal wiring in flies in a variable exon-specific manner. We showed that targeted deletion of the intronic docking site perturbed base pairing-mediated regulation of inclusion of variable exons. Unexpectedly, we generated mutant flies with normal overall Dscam1 protein levels and an identical number but global changes in exon 4 and exon 9 isoform bias (DscamΔ4D −/− and DscamΔ9D −/− ), respectively. DscamΔ9D -/mutant exhibited remarkable mushroom body defects, which were correlated with the extent of the disrupted isoform bias. By contrast, the DscamΔ4D -/animals exhibited a much less severe defective phenotype than DscamΔ9D -/animals, suggestive of a variable domain-specific requirement for isoform bias.Importantly, mosaic analysis revealed that changes in isoform bias caused axonal defects but did not influence the self-avoidance of axonal branches. We concluded that, in contrast to the Dscam1 isoform number that provides the molecular basis for neurite self-avoidance, isoform bias may play a non-repulsive role in mushroom body axonal wiring.

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“…Recent studies indicate that competing RNA pairings guarantee that only one variant exon is spliced from a cluster of duplicated exons (Graveley 2005;Anastassiou et al 2006;May et al 2011;Yang et al 2011;Suyama 2013;Yue et al 2016bYue et al , 2017Hatje et al 2017;Jin et al 2018). This mechanism was initially proposed in the exon 6 cluster of Drosophila Dscam, which is involved in two types of intronic elements: the docking site and selector sequences (Graveley 2005).…”

Section: Introductionmentioning

confidence: 99%

Competing RNA pairings in complex alternative splicing of a 3′ variable region

Pan

Shi

Chen

et al. 2018

RNA

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Alternative pre-mRNA splicing remarkably expands protein diversity in eukaryotes. can generate three major 3' splice isoforms that exhibit distinct innate immune recognition and defenses against various microbial infections. However, the regulatory mechanisms underlying the uniquely biased splicing pattern at the 3' variable region remain unclear. Here we show that competing RNA pairings control the unique splicing of the 3' variable region of pre-mRNA. We reveal three roles by which these RNA pairings jointly regulate the 3' variant selection through activating the proximal 3' splice site and concurrently masking the intron-proximal 5' splice site, in combination with physical competition of RNA pairing. We also reveal that competing RNA pairings regulate alternative splicing of the highly complex 3' variable regions of and Our findings will facilitate a better understanding of the regulatory mechanisms of highly complex alternative splicing as well as highly variable 3' processing.

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Long-range RNA pairings contribute to mutually exclusive splicing

Cited by 27 publications

References 47 publications

Mutually exclusive alternative splicing of pre‐mRNAs

Mutually exclusive alternative splicing of pre‐mRNAs

Intron-targeted mutagenesis reveals roles forDscam1RNA pairing-mediated splicing bias in neuronal wiring

Competing RNA pairings in complex alternative splicing of a 3′ variable region

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