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Full-length transcript characterization of SF3B1 mutation in chronic lymphocytic leukemia reveals downregulation of retained introns

Author

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  • Alison D. Tang

    (University of California)

  • Cameron M. Soulette

    (University of California)

  • Marijke J. van Baren

    (University of California)

  • Kevyn Hart

    (University of California)

  • Eva Hrabeta-Robinson

    (University of California)

  • Catherine J. Wu

    (Dana-Farber Cancer Institute
    Broad Institiute of Harvard and MIT
    Brigham and Women’s Hospital, Harvard Medical School)

  • Angela N. Brooks

    (University of California)

Abstract

While splicing changes caused by somatic mutations in SF3B1 are known, identifying full-length isoform changes may better elucidate the functional consequences of these mutations. We report nanopore sequencing of full-length cDNA from CLL samples with and without SF3B1 mutation, as well as normal B cell samples, giving a total of 149 million pass reads. We present FLAIR (Full-Length Alternative Isoform analysis of RNA), a computational workflow to identify high-confidence transcripts, perform differential splicing event analysis, and differential isoform analysis. Using nanopore reads, we demonstrate differential 3’ splice site changes associated with SF3B1 mutation, agreeing with previous studies. We also observe a strong downregulation of intron retention events associated with SF3B1 mutation. Full-length transcript analysis links multiple alternative splicing events together and allows for better estimates of the abundance of productive versus unproductive isoforms. Our work demonstrates the potential utility of nanopore sequencing for cancer and splicing research.

Suggested Citation

  • Alison D. Tang & Cameron M. Soulette & Marijke J. van Baren & Kevyn Hart & Eva Hrabeta-Robinson & Catherine J. Wu & Angela N. Brooks, 2020. "Full-length transcript characterization of SF3B1 mutation in chronic lymphocytic leukemia reveals downregulation of retained introns," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15171-6
    DOI: 10.1038/s41467-020-15171-6
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    Cited by:

    1. Wei Hu & Yangjun Wu & Qili Shi & Jingni Wu & Deping Kong & Xiaohua Wu & Xianghuo He & Teng Liu & Shengli Li, 2022. "Systematic characterization of cancer transcriptome at transcript resolution," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Sepideh Tavakoli & Mohammad Nabizadeh & Amr Makhamreh & Howard Gamper & Caroline A. McCormick & Neda K. Rezapour & Ya-Ming Hou & Meni Wanunu & Sara H. Rouhanifard, 2023. "Semi-quantitative detection of pseudouridine modifications and type I/II hypermodifications in human mRNAs using direct long-read sequencing," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Yaqi Su & Zhejian Yu & Siqian Jin & Zhipeng Ai & Ruihong Yuan & Xinyi Chen & Ziwei Xue & Yixin Guo & Di Chen & Hongqing Liang & Zuozhu Liu & Wanlu Liu, 2024. "Comprehensive assessment of mRNA isoform detection methods for long-read sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Yuchao Xia & Zijie Jin & Chengsheng Zhang & Linkun Ouyang & Yuhao Dong & Juan Li & Lvze Guo & Biyang Jing & Yang Shi & Susheng Miao & Ruibin Xi, 2023. "TAGET: a toolkit for analyzing full-length transcripts from long-read sequencing," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Kensuke Yamaguchi & Kazuyoshi Ishigaki & Akari Suzuki & Yumi Tsuchida & Haruka Tsuchiya & Shuji Sumitomo & Yasuo Nagafuchi & Fuyuki Miya & Tatsuhiko Tsunoda & Hirofumi Shoda & Keishi Fujio & Kazuhiko , 2022. "Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Jun Inamo & Akari Suzuki & Mahoko Takahashi Ueda & Kensuke Yamaguchi & Hiroshi Nishida & Katsuya Suzuki & Yuko Kaneko & Tsutomu Takeuchi & Hiroaki Hatano & Kazuyoshi Ishigaki & Yasushi Ishihama & Kazu, 2024. "Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Michal Kabza & Alexander Ritter & Ashley Byrne & Kostianna Sereti & Daniel Le & William Stephenson & Timothy Sterne-Weiler, 2024. "Accurate long-read transcript discovery and quantification at single-cell, pseudo-bulk and bulk resolution with Isosceles," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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