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Single-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes

Author

Listed:
  • Chenchen Zhu

    (Stanford University)

  • Jingyan Wu

    (Stanford University)

  • Han Sun

    (Stanford University)

  • Francesca Briganti

    (Genome Biology Unit
    Stanford University
    Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences)

  • Benjamin Meder

    (Stanford University
    University of Heidelberg
    partner site Heidelberg
    University of Heidelberg)

  • Wu Wei

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences
    Shanghai Jiao Tong University
    Stanford University)

  • Lars M. Steinmetz

    (Stanford University
    Genome Biology Unit
    Stanford University
    Stanford University)

Abstract

Alternative splicing generates differing RNA isoforms that govern phenotypic complexity of eukaryotes. Its malfunction underlies many diseases, including cancer and cardiovascular diseases. Comparative analysis of RNA isoforms at the genome-wide scale has been difficult. Here, we establish an experimental and computational pipeline that performs de novo transcript annotation and accurately quantifies transcript isoforms from cDNA sequences with a full-length isoform detection accuracy of 97.6%. We generate a searchable, quantitative human transcriptome annotation with 31,025 known and 5,740 novel transcript isoforms ( http://steinmetzlab.embl.de/iBrowser/ ). By analyzing the isoforms in the presence of RNA Binding Motif Protein 20 (RBM20) mutations associated with aggressive dilated cardiomyopathy (DCM), we identify 121 differentially expressed transcript isoforms in 107 cardiac genes. Our approach enables quantitative dissection of complex transcript architecture instead of mere identification of inclusion or exclusion of individual exons, as exemplified by the discovery of IMMT isoforms mis-spliced by RBM20 mutations. Thereby we achieve a path to direct differential expression testing independent of an existing annotation of transcript isoforms, providing more immediate biological interpretation and higher resolution transcriptome comparisons.

Suggested Citation

  • Chenchen Zhu & Jingyan Wu & Han Sun & Francesca Briganti & Benjamin Meder & Wu Wei & Lars M. Steinmetz, 2021. "Single-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24484-z
    DOI: 10.1038/s41467-021-24484-z
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    Cited by:

    1. Julia Kornienko & Marta Rodríguez-Martínez & Kai Fenzl & Florian Hinze & Daniel Schraivogel & Markus Grosch & Brigit Tunaj & Dominik Lindenhofer & Laura Schraft & Moritz Kueblbeck & Eric Smith & Chad , 2023. "Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. 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.
    3. Markus Grosch & Laura Schraft & Adrian Chan & Leonie Küchenhoff & Kleopatra Rapti & Anne-Maud Ferreira & Julia Kornienko & Shengdi Li & Michael H. Radke & Chiara Krämer & Sandra Clauder-Münster & Emer, 2023. "Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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