Transcriptome-wide modulation of splicing by the exon junction complex

Wang, Zhen; Murigneux, Valentine; Hir, Hervé Le

doi:10.1186/s13059-014-0551-7

Cited by 85 publications

(73 citation statements)

References 72 publications

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“…Depletion of the EJC proteins causes changes in splicing patterns in Drosophila and other organisms (Ashton-Beaucage et al, 2010; Hayashi et al, 2014; Malone et al, 2014; Michelle et al, 2012; Roignant and Treisman, 2010; Wang et al, 2014). These changes can be interpreted in two ways: either canonical EJC deposition can influence splicing of neighbouring introns or the EJC proteins can affect splice site recognition by being functional components of pre-spliceosome intermediates.…”

Section: Discussionmentioning

confidence: 99%

Exon junction complex proteins bind nascent transcripts independently of pre-mRNA splicing in Drosophila melanogaster

Choudhury

Singh

McLeod

et al. 2016

eLife

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Although it is currently understood that the exon junction complex (EJC) is recruited on spliced mRNA by a specific interaction between its central protein, eIF4AIII, and splicing factor CWC22, we found that eIF4AIII and the other EJC core proteins Y14 and MAGO bind the nascent transcripts of not only intron-containing but also intronless genes on Drosophila polytene chromosomes. Additionally, Y14 ChIP-seq demonstrates that association with transcribed genes is also splicing-independent in Drosophila S2 cells. The association of the EJC proteins with nascent transcripts does not require CWC22 and that of Y14 and MAGO is independent of eIF4AIII. We also show that eIF4AIII associates with both polysomal and monosomal RNA in S2 cell extracts, whereas Y14 and MAGO fractionate separately. Cumulatively, our data indicate a global role of eIF4AIII in gene expression, which would be independent of Y14 and MAGO, splicing, and of the EJC, as currently understood.DOI: http://dx.doi.org/10.7554/eLife.19881.001

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Section: Discussionmentioning

confidence: 99%

Exon junction complex proteins bind nascent transcripts independently of pre-mRNA splicing in Drosophila melanogaster

Choudhury

Singh

McLeod

et al. 2016

eLife

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“…Genomic studies in mammalian cells further support a global function for core EJC components in mRNA splicing (Wang et al, 2014). Wang et al (2014) observed splicing defects with knockdown of EIF4A3, RBM8A and CASC3 in HeLa cells. The observation that CASC3 influences splicing in human cells but not Drosophila, could be due to species or cell specific differences.…”

Section: Introductionmentioning

confidence: 93%

“…Splicing regulation is thought to occur via mechanisms in which EJCs define and influence the splicing of neighboring introns (Hayashi et al, 2014). Genomic studies in mammalian cells further support a global function for core EJC components in mRNA splicing (Wang et al, 2014). Wang et al (2014) observed splicing defects with knockdown of EIF4A3, RBM8A and CASC3 in HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

The exon junction complex in neural development and neurodevelopmental disease

McMahon

Miller

Silver

2016

Intl J of Devlp Neuroscience

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Post-transcriptional mRNA metabolism has emerged as a critical regulatory nexus in proper development and function of the nervous system. In particular, recent studies highlight roles for the exon junction complex (EJC) in neurodevelopment. The EJC is an RNA binding complex composed of 3 core proteins, EIF4A3 (DDX48), RBM8A (Y14), and MAGOH, and is a major hub of post-transcriptional regulation. Following deposition onto mRNA, the EJC serves as a platform for the binding of peripheral factors which together regulate splicing, nonsense mediated decay, translation, and RNA localization. While fundamental molecular roles of the EJC have been well established, the in vivo relevance, particularly in mammals, has only recently been examined. New genetic models and cellular assays have revealed core and peripheral EJC components play critical roles in brain development, stem cell function, neuronal outgrowth, and neuronal activity. Moreover, human genetics studies increasingly implicate EJC components in the etiology of neurodevelopmental disorders. Collectively, these findings indicate that proper dosage of EJC components is necessary for diverse aspects of neuronal development and function. Going forward, genetic models of EJC components will provide valuable tools for further elucidating functions in the nervous system relevant for neurodevelopmental disease.

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“…This default is meant to provide a reasonably stringent baseline. The RNA-seq data for eIF4A3, described in Wang et al (2014), were downloaded from GEO (GSE63091) and data were analyzed similarly to Acinus RNA-seq data. Significant events detected in Acinus or eIF4A3 RNA-seq were compared as described below.…”

Section: Splicingmentioning

confidence: 99%

The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation

Rodor

Pan

Blencowe

et al. 2016

RNA

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Acinus (apoptotic chromatin condensation inducer in the nucleus) is an RNA-binding protein (RBP) originally identified for its role in apoptosis. It was later found to be an auxiliary component of the exon junction complex (EJC), which is deposited at exon junctions as a consequence of pre-mRNA splicing. To uncover the cellular functions of Acinus and investigate its role in splicing, we mapped its endogenous RNA targets using the cross-linking immunoprecipitation protocol (iCLIP). We observed that Acinus binds to pre-mRNAs, associating specifically to a subset of suboptimal introns, but also to spliced mRNAs. We also confirmed the presence of Acinus as a peripheral factor of the EJC. RNA-seq was used to investigate changes in gene expression and alternative splicing following siRNA-mediated depletion of Acinus in HeLa cells. This analysis revealed that Acinus is preferentially required for the inclusion of specific alternative cassette exons and also controls the faithful splicing of a subset of introns. Moreover, a large number of splicing changes can be related to Acinus binding, suggesting a direct role of Acinus in exon and intron definition. In particular, Acinus regulates the splicing of DFFA/ICAD transcript, a major regulator of DNA fragmentation. Globally, the genome-wide identification of RNA targets of Acinus revealed its role in splicing regulation as well as its involvement in other cellular pathways, including cell cycle progression. Altogether, this study uncovers new cellular functions of an RBP transiently associated with the EJC.

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Transcriptome-wide modulation of splicing by the exon junction complex

Cited by 85 publications

References 72 publications

Exon junction complex proteins bind nascent transcripts independently of pre-mRNA splicing in Drosophila melanogaster

Exon junction complex proteins bind nascent transcripts independently of pre-mRNA splicing in Drosophila melanogaster

The exon junction complex in neural development and neurodevelopmental disease

The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation

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