Journal Article

DZNE-2020-00029

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Changes in m6A RNA methylation contribute to heart failure progression by modulating translation.

Berulava, T. (First author)DZNE* ; Buchholz, E. ; Elerdashvili, V.DZNE* ; Pena Centeno, T.DZNE* ; Islam, R.DZNE* ; Lbik, D. ; Mohamed, B. A. ; Renner, A. ; von Lewinski, D. ; Sacherer, M. ; Bohnsack, K. E. ; Bohnsack, M. T. ; Jain, G.DZNE* ; Capece, V.DZNE* ; Cleve, N.DZNE* ; Burkhardt, S.DZNE* ; Hasenfuss, G. ; Fischer, A. (Corresponding author)DZNE* ; Toischer, K. (Last author)DZNE*

2020
Wiley Oxford

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Please use a persistent id in citations: doi:10.1002/ejhf.1672

Abstract: 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.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.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.

Keyword(s): Animals (MeSH) ; Epigenesis, Genetic (MeSH) ; Heart Failure: genetics (MeSH) ; Methylation (MeSH) ; Mice (MeSH) ; RNA: genetics (MeSH) ; RNA: metabolism (MeSH) ; RNA, Messenger: genetics (MeSH)

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer 1 ; AG Fischer)
2. Göttingen common (Göttingen common)
3. Bioinformatics and Genome Dynamics Core (Bioinformatics and Genome Dynamics Core)
4. Computational Systems Biology (AG Bonn 2 ; AG Bonn 2)
5. RNAome database (RNAome database)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Ebsco Academic Search ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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