m6A-mRNA methylation regulates cardiac gene expression and cellular growth

Vivien Kmietczyk; Eva Riechert; Laura Kalinski; Etienne Boileau; Ellen Malovrh; Brandon Malone; Agnieszka Gorska; Christoph Hofmann; Eshita Varma; Lonny Jürgensen; Verena Kamuf-Schenk; Janine Altmüller; Rewati Tappu; Martin Busch; Patrick Most; Hugo A Katus; Christoph Dieterich; Mirko Völkers

doi:10.26508/lsa.201800233

m⁶A-mRNA methylation regulates cardiac gene expression and cellular growth

Life Sci Alliance. 2019 Apr 9;2(2):e201800233. doi: 10.26508/lsa.201800233. Print 2019 Apr.

Authors

Vivien Kmietczyk^{1

2}, Eva Riechert^{1

2}, Laura Kalinski^{1

2}, Etienne Boileau^{1

2

3}, Ellen Malovrh^{1

2}, Brandon Malone^{1

2

3}, Agnieszka Gorska^{1

2}, Christoph Hofmann^{1

2}, Eshita Varma^{1

2}, Lonny Jürgensen^{1

2}, Verena Kamuf-Schenk^{1

2}, Janine Altmüller^{4

5}, Rewati Tappu^{1

2}, Martin Busch^{1

2}, Patrick Most^{1

2}, Hugo A Katus^{1

2}, Christoph Dieterich^{1

2

3}, Mirko Völkers^{6

2}

Affiliations

¹ Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.
² DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
³ Section of Bioinformatics and Systems Cardiology, Department of Cardiology, Angiology, and Pneumology and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany.
⁴ Cologne Center for Genomics, University Cologne, Cologne, Germany.
⁵ Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
⁶ Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany mirko.voelkers@med.uni-heidelberg.de.

Abstract

Conceptually similar to modifications of DNA, mRNAs undergo chemical modifications, which can affect their activity, localization, and stability. The most prevalent internal modification in mRNA is the methylation of adenosine at the N⁶-position (m⁶A). This returns mRNA to a role as a central hub of information within the cell, serving as an information carrier, modifier, and attenuator for many biological processes. Still, the precise role of internal mRNA modifications such as m⁶A in human and murine-dilated cardiac tissue remains unknown. Transcriptome-wide mapping of m⁶A in mRNA allowed us to catalog m⁶A targets in human and murine hearts. Increased m⁶A methylation was found in human cardiomyopathy. Knockdown and overexpression of the m⁶A writer enzyme Mettl3 affected cell size and cellular remodeling both in vitro and in vivo. Our data suggest that mRNA methylation is highly dynamic in cardiomyocytes undergoing stress and that changes in the mRNA methylome regulate translational efficiency by affecting transcript stability. Once elucidated, manipulations of methylation of specific m⁶A sites could be a powerful approach to prevent worsening of cardiac function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / chemistry*
Animals
Cardiomyopathy, Dilated / genetics*
Cardiomyopathy, Dilated / pathology*
Cell Enlargement*
Cell Proliferation / genetics*
Cell Size
Cells, Cultured
Cohort Studies
Gene Expression Regulation*
Gene Knockdown Techniques
Humans
Male
Methylation
Methyltransferases / genetics
Mice
Myocytes, Cardiac / physiology*
Protein Biosynthesis / genetics
RNA, Messenger / genetics*
Rats

Substances

RNA, Messenger
Methyltransferases
Mettl3 protein, mouse
METTL3 protein, human
Adenosine