Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy

Omar M. Hedaya, Kadiam C. Venkata Subbaiah, Feng Jiang, Li Huitong Xie, Jiangbin Wu, Eng-Soon Khor, Mingyi Zhu, David H. Mathews, Chris Proschel and Peng Yao ()
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Omar M. Hedaya: University of Rochester School of Medicine & Dentistry
Kadiam C. Venkata Subbaiah: University of Rochester School of Medicine & Dentistry
Feng Jiang: University of Rochester School of Medicine & Dentistry
Li Huitong Xie: University of Rochester School of Medicine & Dentistry
Jiangbin Wu: University of Rochester School of Medicine & Dentistry
Eng-Soon Khor: University of Rochester School of Medicine & Dentistry
Mingyi Zhu: University of Rochester School of Medicine & Dentistry
David H. Mathews: University of Rochester School of Medicine & Dentistry
Chris Proschel: University of Rochester School of Medicine & Dentistry
Peng Yao: University of Rochester School of Medicine & Dentistry

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Translation of upstream open reading frames (uORFs) typically abrogates translation of main (m)ORFs. The molecular mechanism of uORF regulation in cells is not well understood. Here, we data-mined human and mouse heart ribosome profiling analyses and identified a double-stranded RNA (dsRNA) structure within the GATA4 uORF that cooperates with the start codon to augment uORF translation and inhibits mORF translation. A trans-acting RNA helicase DDX3X inhibits the GATA4 uORF-dsRNA activity and modulates the translational balance of uORF and mORF. Antisense oligonucleotides (ASOs) that disrupt this dsRNA structure promote mORF translation, while ASOs that base-pair immediately downstream (i.e., forming a bimolecular double-stranded region) of either the uORF or mORF start codon enhance uORF or mORF translation, respectively. Human cardiomyocytes and mice treated with a uORF-enhancing ASO showed reduced cardiac GATA4 protein levels and increased resistance to cardiomyocyte hypertrophy. We further show the broad utility of uORF-dsRNA- or mORF-targeting ASO to regulate mORF translation for other mRNAs. This work demonstrates that the uORF-dsRNA element regulates the translation of multiple mRNAs as a generalizable translational control mechanism. Moreover, we develop a valuable strategy to alter protein expression and cellular phenotypes by targeting or generating dsRNA downstream of a uORF or mORF start codon.

Date: 2023
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DOI: 10.1038/s41467-023-41799-1

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