4.8 Article

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

期刊

NATURE COMMUNICATIONS
卷 14, 期 1, 页码 -

出版社

NATURE PORTFOLIO
DOI: 10.1038/s41467-023-41799-1

关键词

-

向作者/读者索取更多资源

By analyzing ribosome profiling data, researchers identified a dsRNA structure in the uORF of the GATA4 gene that enhances uORF translation and inhibits mORF translation. The RNA helicase DDX3X inhibits the activity of the GATA4 uORF-dsRNA and regulates the translation balance of uORF and mORF. ASOs that disrupt the dsRNA structure promote mORF translation.
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. The GAT4A transcription factor mediates cardiac development. Here the authors identify that the 5 ' UTR of GATA4 mRNA contains a double stranded structure downstream of an upstream open reading frame (uORF) that promotes uORF-mediated suppression of the main ORF.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据