Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Abstract

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.

A role for m6A RNA methylation in heart failure development?

“…In concurrence with the study by Dorn et al, 7 Berulava et al 6 show that deregulation of both methylases and demethylases impacts m6A, as well as cardiac function, but although m6A is affected, levels of methylases and demethylases appear only moderately altered during heart failure development. Future studies may therefore focus on the mechanisms that determine which RNAs become hyper-vs. hypomethylated and what determines whether that will affect RNA turnover, protein production or drive, for example, alternative mRNA splicing.…”

“…Future studies may therefore focus on the mechanisms that determine which RNAs become hyper-vs. hypomethylated and what determines whether that will affect RNA turnover, protein production or drive, for example, alternative mRNA splicing. The differences in m6A's effects on mRNA stability in the ischaemia-induced heart failure model presented by Mathiyalagan et al 8 on the one hand, and on mRNA translation in the pressure overload model presented by Berulava et al 6 on the other hand, may provide a starting point for such mechanistic studies.…”

“…In this issue of the Journal, Berulava and colleagues report the results of a study aiming to address a potential role of m6A RNA methylation in heart failure development. 6 The authors observed that changes in m6A RNA methylation affect RNA translation and protein production and are involved in heart failure progression. These results are novel and support an important role of epigenetics mechanisms in general and m6A RNA methylation in particular in the development of heart failure.…”

“…7,8 Although both the current study, and the study by Mathiyalagan et al 8 show changes in global changes in the m6A landscape and in cardiac protein synthesis during heart failure, different mechanisms for the potential functionality of m6A are reported. Where Mathiyalagan et al 8 report changes in messenger RNA (mRNA) stability, Berulava et al 6 demonstrate that changes in protein expression are mostly the consequence of changes in polysome binding and thus in protein translation. The main difference between the two studies is the onset of heart failure; where Mathiyalagan et al focus on very acute tissue damage induced by ischaemia, Berulava et al choose to induce heart failure using pressure overload.…”

“…Noteworthy, collaboration of experts from both the brain and heart fields represents an invaluable resource to study the brain-heart axis, as the old concept of neurocardiology 11 may be reborn as a new field of investigation for the EU-CardioRNA COST Action (www.cardiorna.eu). 12 Berulava et al 6 provide an intriguing dataset, but also leave us with several important questions. The authors demonstrate that m6A impacts polysome binding and protein synthesis.…”