ArticleNature communications2023
Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 34 citations in OpenAlex.
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- PKD1 5'UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development.European journal of human genetics : EJHG · 2026Article
- Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.Nature cardiovascular research · 2026Article
- TheInternational journal of molecular sciences · 2025Review
- Modulating splicing in 5' untranslated regions to treat rare haploinsufficient disease.bioRxiv : the preprint server for biology · 2025Article
- Antisense oligonucleotide-mediated upregulation ofMolecular therapy. Nucleic acids · 2025Article
- Structural Characterization ofInternational journal of molecular sciences · 2025Article
- Deep generative optimization of mRNA codon sequences for enhanced mRNA translation and therapeutic efficacy.Nature communications · 2025Article
- Translational Regulation of Plant Stress Responses: Mechanisms, Pathways, and Applications in Bioengineering.Annual review of phytopathology · 2025Review
- Unconventional codon usage bias mediates mRNA translational dynamics in macrophages.PLoS biology · 2025Article
- Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart.International journal of molecular sciences · 2025Review
- Core biological principles and tools stemming from basic Arabidopsis research.The Plant cell · 2025Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.