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

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  • Omar M. Hedaya

    (University of Rochester School of Medicine & Dentistry
    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
    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
    University of Rochester School of Medicine & Dentistry)

  • David H. Mathews

    (University of Rochester School of Medicine & Dentistry
    University of Rochester School of Medicine & Dentistry
    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
    University of Rochester School of Medicine & Dentistry
    University of Rochester School of Medicine & Dentistry
    University of Rochester School of Medicine & Dentistry)

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.

Suggested Citation

  • Omar M. Hedaya & Kadiam C. Venkata Subbaiah & Feng Jiang & Li Huitong Xie & Jiangbin Wu & Eng-Soon Khor & Mingyi Zhu & David H. Mathews & Chris Proschel & Peng Yao, 2023. "Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41799-1
    DOI: 10.1038/s41467-023-41799-1
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    1. Sibylle Schleich & Katrin Strassburger & Philipp Christoph Janiesch & Tatyana Koledachkina & Katharine K. Miller & Katharina Haneke & Yong-Sheng Cheng & Katrin Küchler & Georg Stoecklin & Kent E. Dunc, 2014. "DENR–MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth," Nature, Nature, vol. 512(7513), pages 208-212, August.
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    1. Debjit Khan & Iyappan Ramachandiran & Kommireddy Vasu & Arnab China & Krishnendu Khan & Fabio Cumbo & Dalia Halawani & Fulvia Terenzi & Isaac Zin & Briana Long & Gregory Costain & Susan Blaser & Amand, 2024. "Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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