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Alternative splicing modulation by G-quadruplexes

Georgakopoulos-Soares, Ilias ; Parada, Guillermo E. ; Wong, Hei Yuen ; Medhi, Ragini ; Furlan, Giulia ; Munita, Roberto LU ; Miska, Eric A. ; Kwok, Chun Kit and Hemberg, Martin (2022) In Nature Communications 13(1).
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... (More)

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.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
13
issue
1
article number
2404
publisher
Nature Publishing Group
external identifiers
  • pmid:35504902
  • scopus:85129303989
ISSN
2041-1723
DOI
10.1038/s41467-022-30071-7
language
English
LU publication?
yes
id
a4c1416c-bccd-48ad-9a00-c291f068f8e9
date added to LUP
2022-07-05 14:51:03
date last changed
2024-04-16 14:10:52
@article{a4c1416c-bccd-48ad-9a00-c291f068f8e9,
  abstract     = {{<p>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 &gt;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.</p>}},
  author       = {{Georgakopoulos-Soares, Ilias and Parada, Guillermo E. and Wong, Hei Yuen and Medhi, Ragini and Furlan, Giulia and Munita, Roberto and Miska, Eric A. and Kwok, Chun Kit and Hemberg, Martin}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Alternative splicing modulation by G-quadruplexes}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-30071-7}},
  doi          = {{10.1038/s41467-022-30071-7}},
  volume       = {{13}},
  year         = {{2022}},
}