rG4detector, a novel RNA G-quadruplex predictor, uncovers their impact on stress granule formation

  • Nucleic Acids Res. 2022 Nov 11;50(20):11426-11441. doi: 10.1093/nar/gkac950.
Maor Turner  1 ,  Yehuda M Danino  2  3 ,  Mira Barshai  1 ,  Nancy S Yacovzada  2  3 ,  Yahel Cohen  2  3 ,  Tsviya Olender  2 ,  Ron Rotkopf  4 ,  David Monchaud  5 ,  Eran Hornstein  2  3 ,  Yaron Orenstein  1  6  7
Affiliations
  • 1. School of Electrical and Computer Engineering, Ben-Gurion University of the Negev, Be'er-Sheva 8410501, Israel.
  • 2. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 3. Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 4. Bioinformatics Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 5. Institut de Chimie Moleculaire, ICMUB CNRS UMR 6302, UBFC Dijon, France.
  • 6. Department of Computer Science, Bar-Ilan University, Ramat-Gan 5290002, Israel.
  • 7. The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
PMID: 36350614 DOI: 10.1093/nar/gkac950
Abstract

RNA G-quadruplexes (rG4s) are RNA secondary structures, which are formed by guanine-rich sequences and have important cellular functions. Existing computational tools for rG4 prediction rely on specific sequence features and/or were trained on small datasets, without considering rG4 stability information, and are therefore sub-optimal. Here, we developed rG4detector, a convolutional neural network to identify potential rG4s in transcriptomics data. rG4detector outperforms existing methods in both predicting rG4 stability and in detecting rG4-forming sequences. To demonstrate the biological-relevance of rG4detector, we employed it to study RNAs that are bound by the RNA-binding protein G3BP1. G3BP1 is central to the induction of stress granules (SGs), which are cytoplasmic biomolecular condensates that form in response to a variety of cellular stresses. Unexpectedly, rG4detector revealed a dynamic enrichment of rG4s bound by G3BP1 in response to cellular stress. In addition, we experimentally characterized G3BP1 cross-talk with rG4s, demonstrating that G3BP1 is a bona fide rG4-binding protein and that endogenous rG4s are enriched within SGs. Furthermore, we found that reduced rG4 availability impairs SG formation. Hence, we conclude that rG4s play a direct role in SG biology via their interactions with RNA-binding proteins and that rG4detector is a novel useful tool for rG4 transcriptomics data analyses.

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