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An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression [iCLIP-seq]

ABSTRACT: An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression [iCLIP-seq]

PROVIDER: PRJNA976358 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24741738.fastq.gz	Fastqsanger.gz
	SRR24741739.fastq.gz	Fastqsanger.gz
	SRR24741740.fastq.gz	Fastqsanger.gz

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An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression [iCLIP-seq]

Project description:We previously showed that the germ cell specific nuclear protein RBMXL2 represses cryptic splicing patterns during meiosis and is required for male fertility. RBMXL2 evolved from the X-linked RBMX gene, which is silenced during meiosis due to sex chromosome inactivation. It has been unknown whether RBMXL2 provides a direct replacement for RBMX in meiosis, or whether RBMXL2 evolved to deal with the transcriptionally permissive environment of meiosis. Here we find that RBMX primarily operates as a splicing repressor in somatic cells, and specifically regulates a distinct class of exons that exceed the median human exon size. RBMX protein-RNA interactions are enriched within ultra-long exons, particularly within genes involved in genome stability, and repress the selection of cryptic splice sites that would compromise gene function. These similarities in overall function suggested that RBMXL2 might replace the function of RBMX during meiosis. To test this prediction we carried out inducible expression of RBMXL2 and the more distantly related RBMY protein in somatic cells, finding each could rescue aberrant patterns of RNA processing in response to RBMX depletion. The C-terminal disordered domain of RBMXL2 is sufficient to rescue proper splicing control after RBMX depletion. Our data indicate that RBMX and RBMXL2 have parallel roles in somatic tissues and the germline that must have have been conserved over at least 200 million years of mammalian evolution. We propose RBMX family proteins are particularly important for the splicing inclusion of ultra-long exons because these would be particularly susceptible to disruption by cryptic splice site selection.

2023-09-28 | GSE233497 | GEO

An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression

Project description:An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression

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An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression [RNA-seq]

Project description:An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression [RNA-seq]

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An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression [RNA-seq]

2023-09-28 | GSE158770 | GEO

An anciently diverged family of RNA binding proteins maintain correct splicing of a class of ultra-long exons through cryptic splice site repression.

Project description: Not available

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An anciently diverged family of RNA binding proteins maintain correct splicing of ultra-long exons through cryptic splice site repression

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-28 | GSE233498 | GEO

Human introns contain conserved tissue-specific cryptic poison exons

Project description:Eukaryotic cells express a large number of transcripts from a single gene due to alternative splicing. Despite hundreds of thousands of splice isoforms being annotated in databases, it has been reported that the current exon catalogs remain incomplete. At the same time, introns of human protein-coding genes contain a large number of evolutionarily conserved elements with unknown function. Here, we explore the possibility that some of them represent cryptic exons that are expressed in rare conditions. We identified a group of cryptic exons that are similar to the annotated exons in terms of evolutionary conservation and RNA-seq read coverage in the GTEx dataset. Most of them were poison, i.e. generated an NMD isoform upon inclusion, and many showed signs of tissue-specific and cancer-specific expression and regulation. We performed RNA-seq in A549 cell line treated with cycloheximide to inactivate NMD, and confirmed using qPCR that seven of eight exons tested are, indeed, expressed. This study shows that introns of human protein-coding genes contain cryptic poison exons, which reside in conserved intronic regions and remain not fully annotated due to insufficient representation in RNA-seq libraries.

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CRYPTID-exon: streamlined detection of cryptic exons from RNA-seq data

Project description:Cryptic splicing has emerged as a pervasive feature of mammlian gene expression with recent studies discovering thousands of previously unannotated splice sites. Despite its prevalence, the functional consequences of this hidden layer of splicing remain largely unknown due to challenges in identifying the exact exonic regions introduced into mRNA transcripts. Here, we introduce a novel computational approach, CRYPTID-exon, that accurately predicts exon boundaries by modeling RNA-seq read coverage anchored on empirically derived splice sites. We use CRYPTID-exon to identify and characterize thousands of cryptic exons in nascent and mature RNA from human cells. Additionally, we demonstrate that CRYPTID-exon is well powered to identify exons that are sensitive to translation-mediated degradation processes. Finally, given the growing interest in leveraging cryptic exons to modulate gene expression levels, we use our approach to identify cryptic exons in disease-relevant genes. We see that targeting these exons with splice-switching antisense oligonucleotides (ASOs) can alter gene expression and splicing patterns of the parent genes. Our study provides a framework to systematically identify and characterize cryptic exons, which will enable downstream insights into their impact on mRNA stability and translation.

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Inhibition of nonsense-mediated decay in TDP-43 deficient neurons reveals novel cryptic exons

Project description:Transactive response DNA binding protein 43 kDa (TDP-43) is a protein that regulates splicing, the loss of which underlies the pathophysiology of a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). In disease states, TDP-43 is cleared from the nucleus of neurons, leading to the loss of its splicing repressor function and the aberrant inclusion of cryptic exons. Frequent inclusion of premature termination codons (PTCs) by cryptic exons leads to degradation of cryptic mRNA by nonsense-mediated mRNA decay (NMD). However, detection of cryptic exons relies on inefficient NMD; therefore cryptic exons efficiently targeted and eliminated by NMD remain undetectable through conventional RNA-sequencing. Here we generated a comprehensive set of neuronal targets of TDP-43 in human IPSC-derived i3Neurons (i3N) by combining TDP-43 knockdown with inhibition of several factors regulating NMD, and identified various cryptic exons that were either underestimated or entirely undetected by TDP-43 knockdown alone.

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Human introns contain conserved tissue-specific cryptic poison exons

Project description:Human introns contain conserved tissue-specific cryptic poison exons

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