P1621m6A RNA-methylation in the progression of heart failure

Abstract Introduction N6-Methyladenosine (m6A) is the most abundant modification of RNA and was found to be a dynamic and reversible process. It is found in many classes of RNA, such as mRNA, noncodingRNA (ncRNA) and microRNA (miR). mRNA methylation can affect splicing, transport and storage or decay, ncRNA methylation might influence signal transduction directly as well as it might affect miR interference. Deregulation of such epigenetic processes and aberrant gene expressions are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA-methylation in cardiac hypertrophy and heart failure development. Methods and results m6A RNA-methylation was analysed via methylated RNA immunoprecipitation (meRIP) and subsequent next generation sequencing (NGS). Our data shows that approximately one quarter of the transcripts in the healthy mouse (24.09%) and human heart (14.6%) exhibit m6A RNA-methylation. A mild positive correlation of m6A RNA-methylation at the 5'UTR and coding region with transcript level was observed while m6A RNA-methylation at the 3'UTR showed a mild negative correlation. We analysed heart failure in mice and humans and observed that changes in m6A RNA-methylation exceed changes in gene-expression (in human data 1219 differentially methylated and 198 diff. expressed, with 30 showing changes in both methylation and expression; in mouse data 1135 diff. methylated and 127 diff. expressed, with 47 showing changes in both methylation and expression). In mouse and human heart failure, transcripts with altered m6A RNA-methylation were mainly linked to metabolic and regulatory pathways while changes in transcript level mainly represented changes in structural plasticity. In the diseased state m6A RNA-methylation showed no correlation to transcript level. To gain further insight into m6A mediated effects on the translational level, polysome-sequencing was applied. These data provide evidence that in the diseased heart changes in m6A RNA-methylation affect RNA translation, represented by a positive correlation (r=0.37, p=2.2e-16) of log2fc changes in translation and m6A methylation. Conclusions Our study describes m6A RNA-methylation at the genome-wide level in the human heart. The mouse model provides evidence that changes in m6A RNA-methylation plays an important role in heart failure development by affecting regulatory pathways distinct from those genes with altered expression levels. Our data suggest that modulation of epitranscriptomic processes such as m6A-methylation might be an interesting target for therapeutic interventions. Acknowledgement/Funding CRC 1002