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Global donor and acceptor splicing site kinetics in human cells

  1. Leonhard Wachutka
  2. Livia Caizzi
  3. Julien Gagneur  Is a corresponding author
  4. Patrick Cramer  Is a corresponding author
  1. Technical University of Munich, Germany
  2. Max Planck Institute for Biophysical Chemistry, Germany
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Cite this article as: eLife 2019;8:e45056 doi: 10.7554/eLife.45056

Abstract

RNA splicing is an essential part of eukaryotic gene expression. Although the mechanism of splicing has been extensively studied in vitro, in vivo kinetics for the two-step splicing reaction remain poorly understood. Here we combine transient transcriptome sequencing (TT-seq) and mathematical modeling to quantify RNA metabolic rates at donor and acceptor splice sites across the human genome. Splicing occurs in the range of minutes and is limited by the speed of RNA polymerase elongation. Splicing kinetics strongly depends on the position and nature of nucleotides flanking splice sites, and on structural interactions between unspliced RNA and small nuclear RNAs in spliceosomal intermediates. Finally, we introduce the 'yield' of splicing as the efficiency of converting unspliced to spliced RNA and show that it is highest for mRNAs and independent of splicing kinetics. These results lead to quantitative models describing how splicing rates are encoded in the human genome.

Data availability

The sequencing data and processed files were deposited in NCBI Gene Expression Omnibus (GEO) database under accession code GSE129635.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Leonhard Wachutka

    Department of Informatics, Technical University of Munich, Garching, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5959-040X
  2. Livia Caizzi

    Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9723-6893
  3. Julien Gagneur

    Department of Informatics, Technical University of Munich, Garching, Germany
    For correspondence
    gagneur@in.tum.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8924-8365
  4. Patrick Cramer

    Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    For correspondence
    patrick.cramer@mpibpc.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5454-7755

Funding

European Molecular Biology Organization (ALTF-1261-2014)

  • Livia Caizzi

Horizon 2020 SOUND (633974)

  • Leonhard Wachutka
  • Julien Gagneur

European Research Council

  • Patrick Cramer

Volkswagen Foundation

  • Patrick Cramer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Douglas L Black, University of California, Los Angeles, United States

Publication history

  1. Received: January 20, 2019
  2. Accepted: April 25, 2019
  3. Accepted Manuscript published: April 26, 2019 (version 1)
  4. Version of Record published: June 4, 2019 (version 2)

Copyright

© 2019, Wachutka et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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