Intron retention is a widespread mechanism of tumor-suppressor inactivation

Jung, Hyunchul; Lee, Dong‐Hoon; Lee, Jongkeun; Park, Donghyun; Kim, Yeon Jeong; Park, Woong-Yang; Hong, Dong Ho; Park, Peter J.; Lee, Eunjung

doi:10.1038/ng.3414

Cited by 311 publications

(333 citation statements)

References 67 publications

(45 reference statements)

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“…It has been suggested that IR is deliberately used as a regulatory step to decrease the expression of target genes (BRAUNSCHWEIG et al 2014;JUNG et al 2015).Our data showed that the majority of sex-biased IR events located in CDS introduced PTCs (> 80%, Figure 2D). We therefore asked whether sex-biased IR events with PTC are associated with gene expression changes.…”

Section: Introns That Are Differentially Retained In Ovary and Testismentioning

confidence: 58%

“…Recent studies have identified numerous differentially regulated AS events in a variety of conditions (MCINTYRE et al 2006;WANG et al 2008;TELONIS-SCOTT et al 2009;GAN et al 2010;CHANG et al 2011;HARTMANN et al 2011;STURGILL et al 2013;WANG et al 2014) and highlighted the role of IR as a cellular mechanism to influence mRNA abundance and alter biological outcomes (BRAUNSCHWEIG et al 2014;JUNG et al 2015;EDWARDS et al 2016;MAUGER et al 2016;NI et al 2016;MIDDLETON et al 2017;NARO et al 2017). However, the occurrence and extent of sex-biased IR has not been addressed and the role of sex chromosomes in the modulation of splicing has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Because of this, mRNAs generated through IR events could be viewed as failures of the splicing process and void of biological function (JAILLON et al 2008;ROY AND IRIMIA 2008). However, recent studies suggested that IR events are involved in multiple cellular and physiological processes, including hematogenesis (WONG et al 2013;EDWARDS et al 2016;PIMENTEL et al 2016), T cell activation (NI et al 2016), neuronal differentiation (BRAUNSCHWEIG et al 2014), and carcinogenesis (DVINGE AND BRADLEY 2015;JUNG et al 2015). Despite these advances, questions remain regarding the extent to which introns are differentially retained between sexes and how sex-biased IR rates are regulated.…”

Section: Introductionmentioning

confidence: 99%

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The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

Wang¹,

Branco²,

Lemos³

2018

Genetics

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The Drosophila Y chromosome is a 40MB segment of mostly repetitive DNA; it harbors a handful of protein coding genes and a disproportionate amount of satellite repeats, transposable elements, and multicopy DNA arrays. Intron retention (IR) is a type of alternative splicing (AS) event by which one or more introns remain within the mature transcript. IR recently emerged as a deliberate cellular mechanism to modulate gene expression levels and has been implicated in multiple biological processes. However, the extent of sex differences in IR and the contribution of the Y chromosome to the modulation of alternative splicing and intron retention rates has not been addressed. Here we showed pervasive intron retention (IR) in the fruit fly Drosophila melanogaster with thousands of novel IR events, hundreds of which displayed extensive sex-bias.

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Section: Introns That Are Differentially Retained In Ovary and Testismentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

Wang¹,

Branco²,

Lemos³

2018

Genetics

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“…Recent work, however, has shown that intron retention might be a conserved and more common mode of transcript regulation than previously appreciated (Galante et al 2004;Braunschweig et al 2014;Boutz et al 2015;Mudvari et al 2015;Wong et al 2016), with examples found in hematopoiesis (Wong et al 2013;Edwards et al 2016), T-cell activation (Ni et al 2016), and neuronal development and activity (Bell et al 2010;Yang et al 2012;Yap et al 2012). Inappropriate intron retention has also been identified in diverse genetic diseases, including cancer (Seifert et al 2006;Tanackovic et al 2011;Dvinge and Bradley 2015;Jung et al 2015;Ortega-Recalde et al 2015;Kallabi et al 2016). Although there are tools that can predict the effects of sequence variants on alternative exon use or alternative 5 ′ donor or 3 ′ acceptor splice sites (Jian et al 2014), to our knowledge, there are no computational tools to predict intron retention from sequence data.…”

Section: Intron Retention As a Mechanism Of Genetic Diseasementioning

confidence: 99%

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

et al. 2017

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While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the “low hanging fruit” of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

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“…Intron retention regulation has been observed in different cell types (Braunschweig et al 2014), during specific differentiation processes such as erythropoiesis (Pimentel et al 2016) or granulocyte differentiation (Wong et al 2013). Intron retention also plays a role in cancer as a mechanism of tumor suppressor inactivation (Jung et al 2015). Since Acinus controls the splicing of a subset of introns, it could represent a good candidate for the specific control of IR in a precise biological context, as was observed for hnRNPLL in intron retention regulation in T cells (Cho et al 2014).…”

Section: A Role For Acinus In Splicing Regulationmentioning

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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Intron retention is a widespread mechanism of tumor-suppressor inactivation

Cited by 311 publications

References 67 publications

The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

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

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