Gene architecture directs splicing outcome in separate nuclear spatial regions

Tammer, Luna; Hameiri, Ofir; Keydar, Ifat; Roy, Vanessa Rachel; Ashkenazy-Titelman, Asaf; Custódio, Noélia; Sason, Itay; Shayevitch, Ronna; Rodríguez-Vaello, Victoria; Rino, José Pedro; Maor, Galit Lev; Leader, Yodfat; Khair, Doha; Aiden, E; Elkon, Ran; Irimia, Manuel; Sharan, Roded; Shav‐Tal, Yaron; Carmo‐Fonseca, Maria; Ast, Gil

doi:10.1016/j.molcel.2022.02.001

Cited by 44 publications

(28 citation statements)

References 89 publications

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“…The present study confirms in mouse liver that the efficiency of exon usage by the splicing machinery in Dido1 E16 mutants depends greatly on downstream thymidine abundance. A similar type of compositional bias was recently reported to control exon usage through divergent modes of splicing, either by intron definition or exon definition, in an independent system [ 30 ].…”

Section: Discussionmentioning

confidence: 60%

Hepatitis, testicular degeneration, and ataxia in DIDO3-deficient mice with altered mRNA processing

2022

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Background mRNA processing is an essential step of gene expression; its malfunction can lead to different degrees of physiological disorder from subclinical disease to death. We previously identified Dido1 as a stemness marker and a gene involved in embryonic stem cell differentiation. DIDO3, the largest protein encoded by the Dido1 gene, is necessary for accurate mRNA splicing and correct transcription termination. The deletion of Dido1 exon16, which encodes the carboxy-terminal half of DIDO3, results in early embryonic lethality in mouse. Results We obtained mice bearing a Cre-LoxP conditional version of that deletion and studied the effects of inducing it ubiquitously in adult stages. DIDO3-deficient mice survive the deletion but suffer mild hepatitis, testicular degeneration, and progressive ataxia, in association with systemic alterations in mRNA splicing and transcriptional readthrough. Conclusions These results offer insight into the distinct vulnerabilities in mouse organs following impairment of the mRNA processing machinery, and could aid understanding of human health dependence on accurate mRNA metabolism.

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Section: Discussionmentioning

confidence: 60%

Hepatitis, testicular degeneration, and ataxia in DIDO3-deficient mice with altered mRNA processing

2022

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“…Recent investigations provide further support that both intron definition and exon definition occur in vivo [ 32 , 33 ]. However, these studies present evidence that the mechanism by which splice sites are initially recognized is dictated by the difference in GC content, referred to as GC differential, between the exon and the flanking introns.…”

Section: Discussionmentioning

confidence: 98%

“…However, these studies present evidence that the mechanism by which splice sites are initially recognized is dictated by the difference in GC content, referred to as GC differential, between the exon and the flanking introns. Specifically, two architectures are described, referred to as the ‘differential architecture’ and the ‘leveled architecture’ [ 32 , 33 ]. ‘Differential architecture’ exons have a low GC content, and their flanking introns have an even lower GC content.…”

Section: Discussionmentioning

confidence: 99%

“…Altering the GC content between exon and the downstream intron can be used to alter the mode splice site recognition, without changing the length of the intron. These observations suggest that intron length may not be the determining factor in the mode of splice site recognition for exon definition [ 32 , 33 ]. It will be important for future exon definition studies to consider the GC content across the exon and flanking introns.…”

Section: Discussionmentioning

confidence: 99%

“…We calculated GC content differentials between the LL and SS architectural classes of alternatively spliced 5’ and 3ʹss exons. Remarkably, the intron length-defined LL and SS categories closely resemble the ‘differential’ and ‘leveled’ architectures respectively [ 32 , 33 ] (Supplemental Figure 2). Thus, the GC content, as defined the Amit et al [ 32 ], of long introns (>250 nts) differs significantly from the GC content of short introns (<250 nts), suggesting that GC content or intron size definitions are comparable approaches to define exon and intron definition modes of splice site recognition.…”

Section: Discussionmentioning

confidence: 99%

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Splice site proximity influences alternative exon definition

2022

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Alternative splicing enables higher eukaryotes to expand mRNA diversity from a finite number of genes through highly combinatorial splice site selection mechanisms that are influenced by the sequence of competing splice sites, cis-regulatory elements binding trans-acting factors, the length of exons and introns harbouring alternative splice sites and RNA secondary structures at putative splice junctions. To test the hypothesis that the intron definition or exon definition modes of splice site recognition direct the selection of alternative splice patterns, we created a database of alternative splice site usage (ALTssDB). When alternative splice sites are embedded within short introns (intron definition), the 5′ and 3′ splice sites closest to each other across the intron preferentially pair, consistent with previous observations. However, when alternative splice sites are embedded within large flanking introns (exon definition), the 5′ and 3′ splice sites closest to each other across the exon are preferentially selected. Thus, alternative splicing decisions are influenced by the intron and exon definition modes of splice site recognition. The results demonstrate that the spliceosome pairs splice sites that are closest in proximity within the unit of initial splice site selection.

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ASTK: A Machine Learning‐Based Integrative Software for Alternative Splicing Analysis

Huang,

He,

et al. 2024

Advanced Intelligent Systems

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Alternative splicing (AS) is a fundamental mechanism that regulates gene expressionin both physiological and pathological processes. This article introduces ASTK, a software package covering upstream and downstream analysis of AS. Initially, ASTK offers a module to perform enrichment analysis at both the gene‐ and exon‐level to incorporate various impacts by different spliced events on a single gene. We further cluster AS genes and alternative exons into three groups based on spliced exon sizes (micro‐, mid‐, and macro‐), which are preferentially associated with distinct biological pathways. A major challenge in the field has been decoding the regulatory codes of splicing. ASTK adeptly extracts both sequence features and epigenetic marks associated with AS events. Through the application of machine learning algorithms, we identified pivotal features influencing the inclusion levels of most AS types. Notably, the splice site strength is a primary determinant for the inclusion levels in alternative 3’/5’ splice sites (A3/A5). For the alternative first exon and skipping exon classes, a combination of sequence and epigenetic features collaboratively dictate exon inclusion/exclusion. Our findings underscore ASTK's capability to enhance the functional understanding of AS events and shed light on the intricacies of splicing regulation.

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Gene architecture directs splicing outcome in separate nuclear spatial regions

Cited by 44 publications

References 89 publications

Hepatitis, testicular degeneration, and ataxia in DIDO3-deficient mice with altered mRNA processing

Hepatitis, testicular degeneration, and ataxia in DIDO3-deficient mice with altered mRNA processing

Splice site proximity influences alternative exon definition

ASTK: A Machine Learning‐Based Integrative Software for Alternative Splicing Analysis

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