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

Jing Zhang, Samuel E. Harvey, Chonghui Cheng
doi: https://doi.org/10.1101/434647
Jing Zhang
1Lester & Sue Smith Breast Center, Department of Molecular & Human Genetics, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
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Samuel E. Harvey
1Lester & Sue Smith Breast Center, Department of Molecular & Human Genetics, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
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Chonghui Cheng
1Lester & Sue Smith Breast Center, Department of Molecular & Human Genetics, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
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  • For correspondence: chonghui.cheng@bcm.edu
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ABSTRACT

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. These data suggest the use of emetine and cephaeline for investigating mechanisms of G-quadruplex-associated alternative splicing.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 03, 2018.
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A high-throughput screen identifies small molecule modulators of alternative splicing by targeting RNA G-quadruplexes
Jing Zhang, Samuel E. Harvey, Chonghui Cheng
bioRxiv 434647; doi: https://doi.org/10.1101/434647
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A high-throughput screen identifies small molecule modulators of alternative splicing by targeting RNA G-quadruplexes
Jing Zhang, Samuel E. Harvey, Chonghui Cheng
bioRxiv 434647; doi: https://doi.org/10.1101/434647

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