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Changes in m6A RNA methylation contribute to heart failure progression by modulating translation
Author(s) -
Berulava Tea,
Buchholz Eric,
Elerdashvili Vakhtang,
Pena Tonatiuh,
Islam Md Rezaul,
Lbik Dawid,
Mohamed Belal A.,
Renner Andre,
Lewinski Dirk,
Sacherer Michael,
Bohnsack Katherine E.,
Bohnsack Markus T.,
Jain Gaurav,
Capece Vincenzo,
Cleve Nicole,
Burkhardt Susanne,
Hasenfuss Gerd,
Fischer Andre,
Toischer Karl
Publication year - 2020
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.1672
Subject(s) - rna methylation , rna , demethylase , methylation , biology , epigenetics , messenger rna , dna methylation , gene expression , transcription (linguistics) , microbiology and biotechnology , genetics , gene , methyltransferase , linguistics , philosophy
Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next‐generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription‐independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription‐independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.