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Alternative splicing modulation by G-quadruplexes

Author

Listed:
  • Ilias Georgakopoulos-Soares

    (Wellcome Sanger Institute, Wellcome Genome Campus
    Department of Bioengineering and Therapeutic Sciences, University of California San Francisco)

  • Guillermo E. Parada

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge
    University of Toronto)

  • Hei Yuen Wong

    (City University of Hong Kong, Kowloon Tong)

  • Ragini Medhi

    (University of Cambridge
    University of Cambridge)

  • Giulia Furlan

    (University of Cambridge
    University of Cambridge)

  • Roberto Munita

    (Lund Stem Cell Center, Faculty of Medicine, Lund University)

  • Eric A. Miska

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    University of Cambridge)

  • Chun Kit Kwok

    (City University of Hong Kong, Kowloon Tong
    Shenzhen Research Institute of City University of Hong Kong)

  • Martin Hemberg

    (Wellcome Sanger Institute, Wellcome Genome Campus
    University of Cambridge
    Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital)

Abstract

Alternative splicing is central to metazoan gene regulation, but the regulatory mechanisms are incompletely understood. Here, we show that G-quadruplex (G4) motifs are enriched ~3-fold near splice junctions. The importance of G4s in RNA is emphasised by a higher enrichment for the non-template strand. RNA-seq data from mouse and human neurons reveals an enrichment of G4s at exons that were skipped following depolarisation induced by potassium chloride. We validate the formation of stable RNA G4s for three candidate splice sites by circular dichroism spectroscopy, UV-melting and fluorescence measurements. Moreover, we find that sQTLs are enriched at G4s, and a minigene experiment provides further support for their role in promoting exon inclusion. Analysis of >1,800 high-throughput experiments reveals multiple RNA binding proteins associated with G4s. Finally, exploration of G4 motifs across eleven species shows strong enrichment at splice sites in mammals and birds, suggesting an evolutionary conserved splice regulatory mechanism.

Suggested Citation

  • Ilias Georgakopoulos-Soares & Guillermo E. Parada & Hei Yuen Wong & Ragini Medhi & Giulia Furlan & Roberto Munita & Eric A. Miska & Chun Kit Kwok & Martin Hemberg, 2022. "Alternative splicing modulation by G-quadruplexes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30071-7
    DOI: 10.1038/s41467-022-30071-7
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    References listed on IDEAS

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    1. Ramreddy Tippana & Michael C. Chen & Natalia A. Demeshkina & Adrian R. Ferré-D’Amaré & Sua Myong, 2019. "RNA G-quadruplex is resolved by repetitive and ATP-dependent mechanism of DHX36," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Eric T. Wang & Rickard Sandberg & Shujun Luo & Irina Khrebtukova & Lu Zhang & Christine Mayr & Stephen F. Kingsmore & Gary P. Schroth & Christopher B. Burge, 2008. "Alternative isoform regulation in human tissue transcriptomes," Nature, Nature, vol. 456(7221), pages 470-476, November.
    3. Yoseph Barash & John A. Calarco & Weijun Gao & Qun Pan & Xinchen Wang & Ofer Shai & Benjamin J. Blencowe & Brendan J. Frey, 2010. "Deciphering the splicing code," Nature, Nature, vol. 465(7294), pages 53-59, May.
    4. Enid Yi Ni Lam & Dario Beraldi & David Tannahill & Shankar Balasubramanian, 2013. "G-quadruplex structures are stable and detectable in human genomic DNA," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
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