Recursive splicing is a rare event in the mouse brain

Moon, Sohyun; Zhao, Ying-Tao

doi:10.1371/journal.pone.0263082

Cited by 3 publications

(1 citation statement)

References 39 publications

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“…In addition to the conventional splicing described above, which involves the one‐time removal of introns, there is a remarkable phenomenon known as recursive splicing (RS). This process enables a multistep intron removal and has been identified in Drosophila, 20 mice, 21 and humans, 22 highlighting its biological significance. The mechanics of RS are depicted in Figure 1.…”

Section: Regulatory Factors For Alternative Splicingmentioning

confidence: 99%

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Shi,

Tang,

Xiang

2024

Clinical Genetics

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Accurate pre‐mRNA splicing is essential for proper protein translation; however, aberrant splicing is commonly observed in the context of cancer and genetic disorders. Notably, in genetic diseases, these splicing abnormalities often play a pivotal role. Substantial challenges persist in accurately identifying and classifying disease‐induced aberrant splicing, as well as in development of targeted therapeutic strategies. In this review, we examine prevalent forms of aberrant splicing and explore potential therapeutic approaches aimed at addressing these splicing‐related diseases. This summary contributes to a deeper understanding of the complexities about aberrant splicing and provide a foundation for the development of effective therapeutic interventions in the field of genetic disorders and cancer.

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Section: Regulatory Factors For Alternative Splicingmentioning

confidence: 99%

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Shi,

Tang,

Xiang

2024

Clinical Genetics

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Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1

Moon

Zhao

2022

Human Molecular Genetics

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Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in more than 34 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause the same outcome of KS are not fully understood. Here we show that disruptions of KS-linked genes affect the same biological processes, indicating convergent molecular mechanisms underlying KS. We carried out machine learning-based predictions and found that KS-linked mutations in heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) are likely loss-of-function mutations. We next disrupted Hs6st1 and another KS-linked gene, fibroblast growth factor receptor 1 (Fgfr1), in mouse neuronal cells and measured transcriptome changes using RNA sequencing. We found that disruptions of Hs6st1 and Fgfr1 altered genes in the same biological processes, including the upregulation of genes in extracellular pathways and the downregulation of genes in chromatin pathways. Moreover, we performed genomics and bioinformatics analyses and found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS. Together, our results demonstrate how different KS-linked genes work coordinately in a convergent signaling pathway to regulate the same biological processes, thus providing new insights into KS.

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Is intron removal by recursive splicing necessitated by the evolution of genomic gigantism?

Adams,

Mueller

2024

Preprint

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Splicing of introns is an important step that pre-mRNA transcripts undergo during processing in the nucleus to become mature mRNAs. Although long thought to occur in a single step, introns are now also known to be removed in multiple steps through a process called recursive splicing. This non-canonical form of splicing is hypothesized to increase splicing fidelity, particularly in longer introns. In species that have evolved gigantic genome sizes, overall intron lengths are much longer than in genomes of typical size. Using West African lungfish (Protopterus annectens; genome size ∼40Gb) as a model, we use total RNA-seq data to test the hypothesis that gigantic genomes have shifted to rely predominantly on recursive splicing to manage their long introns. Our results suggest levels of recursive splicing at conserved sites in the lungfish that are similar to those seen in humans, indicating that genome-wide intronic expansion accompanying genomic gigantism does not necessitate ubiquitous use of recursive splicing. However, in addition to these results, we also observed patterns of decreasing RNA-seq read depths across entire intron lengths and note that both canonical co-transcriptional splicing and stochastic recursive splicing using many random splice sites could produce this pattern. Thus, we infer canonical co-transcriptional splicing and/or stochastic recursive splicing – but not ubiquitous recursive splicing at conserved sites – manage the removal of long introns in gigantic genomes. We conclude that the vast increase in intron length in gigantic genomes does not appear to have coincided with a fundamental shift in splicing mechanisms.Statement and DeclarationsThe authors declare no competing interests.

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Recursive splicing is a rare event in the mouse brain

Cited by 3 publications

References 39 publications

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Therapeutic strategies for aberrant splicing in cancer and genetic disorders

Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1

Is intron removal by recursive splicing necessitated by the evolution of genomic gigantism?

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