Alternative splicing modulation by G-quadruplexes

Ilias Georgakopoulos-Soares, Guillermo E. Parada, Hei Yuen Wong, Ragini Medhi, Giulia Furlan, Roberto Munita, Eric A. Miska, Chun Kit Kwok and Martin Hemberg ()
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Ilias Georgakopoulos-Soares: Wellcome Sanger Institute, Wellcome Genome Campus
Guillermo E. Parada: Wellcome Sanger Institute, Wellcome Genome Campus
Hei Yuen Wong: City University of Hong Kong, Kowloon Tong
Ragini Medhi: University of Cambridge
Giulia Furlan: University of Cambridge
Roberto Munita: Lund Stem Cell Center, Faculty of Medicine, Lund University
Eric A. Miska: Wellcome Sanger Institute, Wellcome Genome Campus
Chun Kit Kwok: City University of Hong Kong, Kowloon Tong
Martin Hemberg: Wellcome Sanger Institute, Wellcome Genome Campus

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30071-7

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