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Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia

Author

Listed:
  • Yusuke Shiozawa

    (The University of Tokyo
    Kyoto University)

  • Luca Malcovati

    (University of Pavia
    Fondazione IRCCS Policlinico San Matteo & University of Pavia)

  • Anna Gallì

    (Fondazione IRCCS Policlinico San Matteo & University of Pavia)

  • Aiko Sato-Otsubo

    (Kyoto University)

  • Keisuke Kataoka

    (Kyoto University)

  • Yusuke Sato

    (Kyoto University
    The University of Tokyo)

  • Yosaku Watatani

    (Kyoto University)

  • Hiromichi Suzuki

    (Kyoto University)

  • Tetsuichi Yoshizato

    (Kyoto University)

  • Kenichi Yoshida

    (Kyoto University)

  • Masashi Sanada

    (Nagoya Medical Center)

  • Hideki Makishima

    (Kyoto University)

  • Yuichi Shiraishi

    (The University of Tokyo)

  • Kenichi Chiba

    (The University of Tokyo)

  • Eva Hellström-Lindberg

    (Karolinska Institutet)

  • Satoru Miyano

    (The University of Tokyo
    The University of Tokyo)

  • Seishi Ogawa

    (Kyoto University)

  • Mario Cazzola

    (University of Pavia
    Fondazione IRCCS Policlinico San Matteo & University of Pavia)

Abstract

Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully elucidated. Here we report transcriptomic analyses of 265 bone marrow samples from myelodysplasia patients, followed by a validation using CRISPR/Cas9-mediated gene editing and an assessment of nonsense-mediated decay susceptibility. Small but widespread reduction of intron-retaining isoforms is the most frequent splicing alteration in SF3B1-mutated samples. SF3B1 mutation is also associated with 3′ splice site alterations, leading to the most pronounced reduction of canonical transcripts. Target genes include tumor suppressors and genes of mitochondrial iron metabolism or heme biosynthesis. Alternative exon usage is predominant in SRSF2- and U2AF1-mutated samples. Usage of an EZH2 cryptic exon harboring a premature termination codon is increased in both SRSF2- and U2AF1-mutated samples. Our study reveals a landscape of splicing alterations and precise targets of various spliceosome mutations.

Suggested Citation

  • Yusuke Shiozawa & Luca Malcovati & Anna Gallì & Aiko Sato-Otsubo & Keisuke Kataoka & Yusuke Sato & Yosaku Watatani & Hiromichi Suzuki & Tetsuichi Yoshizato & Kenichi Yoshida & Masashi Sanada & Hideki , 2018. "Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06063-x
    DOI: 10.1038/s41467-018-06063-x
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    Cited by:

    1. Ruiyan Hou & Chung-Chau Hon & Yuanhua Huang, 2023. "CamoTSS: analysis of alternative transcription start sites for cellular phenotypes and regulatory patterns from 5' scRNA-seq data," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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