A high-throughput screen identifies small molecule modulators of alternative splicing by targeting RNA G-quadruplexes

Nucleic Acids Res. 2019 Apr 23;47(7):3667-3679. doi: 10.1093/nar/gkz036.


RNA secondary structures have been increasingly recognized to play an important regulatory role in post-transcriptional gene regulation. We recently showed that RNA G-quadruplexes, which serve as cis-elements to recruit splicing factors, play a critical role in regulating alternative splicing during the epithelial-mesenchymal transition. In this study, we performed a high-throughput screen using a dual-color splicing reporter to identify chemical compounds capable of regulating G-quadruplex-dependent alternative splicing. We identify emetine and its analog cephaeline as small molecules that disrupt RNA G-quadruplexes, resulting in inhibition of G-quadruplex-dependent alternative splicing. Transcriptome analysis reveals that emetine globally regulates alternative splicing, including splicing of variable exons that contain splice site-proximal G-quadruplexes. Our data suggest the use of emetine and cephaeline for investigating mechanisms of G-quadruplex-associated alternative splicing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing / drug effects*
  • Alternative Splicing / genetics
  • Emetine / pharmacology
  • Exons / drug effects
  • G-Quadruplexes / drug effects*
  • High-Throughput Screening Assays
  • Humans
  • Nucleic Acid Conformation / drug effects
  • RNA / chemistry*
  • RNA / drug effects
  • RNA Splicing / drug effects*
  • RNA Splicing / genetics
  • RNA Splicing Factors / chemistry
  • RNA Splicing Factors / genetics
  • Small Molecule Libraries / pharmacology


  • RNA Splicing Factors
  • Small Molecule Libraries
  • RNA
  • Emetine