High-throughput sensitive screening of small molecule modulators of microexon alternative splicing using dual Nano and Firefly luciferase reporters

Andrew J. Best (), Ulrich Braunschweig, Mingkun Wu, Shaghayegh Farhangmehr, Adrian Pasculescu, Justin J. Lim, Lim Caden Comsa, Mark Jen, Jenny Wang, Alessandro Datti, Jeffrey L. Wrana, Sabine P. Cordes, Rima Al-awar, Hong Han and Benjamin J. Blencowe ()
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Andrew J. Best: University of Toronto
Ulrich Braunschweig: University of Toronto
Mingkun Wu: University of Toronto
Shaghayegh Farhangmehr: University of Toronto
Adrian Pasculescu: Mount Sinai Hospital
Justin J. Lim: University of Toronto
Lim Caden Comsa: University of Toronto
Mark Jen: Mount Sinai Hospital
Jenny Wang: Mount Sinai Hospital
Alessandro Datti: University of Perugia
Jeffrey L. Wrana: University of Toronto
Sabine P. Cordes: University of Toronto
Rima Al-awar: University of Toronto
Hong Han: University of Toronto
Benjamin J. Blencowe: University of Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Disruption of alternative splicing frequently causes or contributes to human diseases and disorders. Consequently, there is a need for efficient and sensitive reporter assays capable of screening chemical libraries for compounds with efficacy in modulating important splicing events. Here, we describe a screening workflow employing dual Nano and Firefly luciferase alternative splicing reporters that affords efficient, sensitive, and linear detection of small molecule responses. Applying this system to a screen of ~95,000 small molecules identified compounds that stimulate or repress the splicing of neuronal microexons, a class of alternative exons often disrupted in autism and activated in neuroendocrine cancers. One of these compounds rescues the splicing of several analyzed microexons in the cerebral cortex of an autism mouse model haploinsufficient for Srrm4, a major activator of brain microexons. We thus describe a broadly applicable high-throughput screening system for identifying candidate splicing therapeutics, and a resource of small molecule modulators of microexons with potential for further development in correcting aberrant splicing patterns linked to human disorders and disease.

Date: 2024
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DOI: 10.1038/s41467-024-50399-6

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