Role of mRNA Modifications in Cardiac Remodeling
Final Report Abstract
The goal of this proposal was to characterize the impact of m6A mRNA methylations on cardiac gene expression control and cardiac function during heart failure. Independent of the etiology, heart failure involves changes in cardiac structure, contractile dysfunction, as well as multiple genetic, and molecular alterations that impact heart function and patient survival. These changes have been referred to as cardiac remodeling. Up- or down-regulation of specific sets of genes are stereotypical patterns of heart failure independent of the etiology. The most prevalent internal modification on mRNA is N6-methyladenosine (m6A). m6A modification is installed by m6A writers, is reversed by erasers, and is read by specific reader proteins. 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, in addition to transferring the message from the DNA. The role of the methylase Mettl3 during cardiac remodeling was analyzed and the results showed that m6A regulates and affects cardiomyocyte fate by adding a posttranscriptional regulation step to gene expression by influencing mRNA stability and translation efficiency. Using Ribo-seq, we identified subsets of mRNAs which are translationally dependent on methylation status or Mettl3 activity. Our findings support the paradigm that mRNA modifications in the heart play important roles in the heart by 1) validating the expression of Mettl3 and Fto in the myocardium, 2) demonstrating dynamic mRNA methylome in heart failure both in human and murine hearts, 3) showing effects upon cell growth in vitro and in vivo, and 4) providing evidence that mRNA methylation also influences mRNA stability and translation in the heart. We also characterized Mettl3 as a key cardiac methylase that regulates cardiac m6A levels and growth control. The exact mechanisms how Mettl3 regulates cellular growth, and which specific targets are responsible for the phenotypic consequences are still unknown and focus of ongoing investigations. Additional studies will be also needed to fully understand whether m6A dependent gene expression causally contributes to cardiac function during pathological remodeling. Once specific targets will be elucidated, manipulations of m6A levels could be a powerful approach to prevent worsening of cardiac function. It may become possible to alter mRNA modifications therapeutically by engineering RNA modifying enzymes with altered substrate specificity, or to test whether novel small molecules that affect the formation of mRNA modifications have therapeutic values. Those approaches will open exciting prospects of developing new therapies for diseases caused by m6A dysregulations including heart diseases.
Publications
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m6A-mRNA methylation regulates cardiac gene expression and cellular growth. Life Science Alliance, 2(2), e201800233.
Kmietczyk, Vivien; Riechert, Eva; Kalinski, Laura; Boileau, Etienne; Malovrh, Ellen; Malone, Brandon; Gorska, Agnieszka; Hofmann, Christoph; Varma, Eshita; Jürgensen, Lonny; Kamuf-Schenk, Verena; Altmüller, Janine; Tappu, Rewati; Busch, Martin; Most, Patrick; Katus, Hugo A; Dieterich, Christoph & Völkers, Mirko
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Monitoring Cell-Type–Specific Gene Expression Using Ribosome Profiling In Vivo During Cardiac Hemodynamic Stress. Circulation Research, 125(4), 431-448.
Doroudgar, Shirin; Hofmann, Christoph; Boileau, Etienne; Malone, Brandon; Riechert, Eva; Gorska, Agnieszka A.; Jakobi, Tobias; Sandmann, Clara; Jürgensen, Lonny; Kmietczyk, Vivien; Malovrh, Ellen; Burghaus, Jana; Rettel, Mandy; Stein, Frank; Younesi, Fereshteh; Friedrich, Ulrike A.; Mauz, Victoria; Backs, Johannes; Kramer, Günter; ... & Völkers, Mirko
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Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes. Cell Reports, 35(6), 109100.
Riechert, Eva; Kmietczyk, Vivien; Stein, Frank; Schwarzl, Thomas; Sekaran, Thileepan; Jürgensen, Lonny; Kamuf-Schenk, Verena; Varma, Eshita; Hofmann, Christoph; Rettel, Mandy; Gür, Kira; Ölschläger, Julie; Kühl, Friederike; Martin, Judit; Ramirez-Pedraza, Marta; Fernandez, Mercedes; Doroudgar, Shirin; Méndez, Raúl; Katus, Hugo A.; ... & Völkers, Mirko
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N6-Methyladenosine in the Heart. RNA Technologies (2021), 309-323. American Geophysical Union (AGU).
Kmietczyk, Vivien; Malovrh, Ellen & Völkers, Mirko
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RNA modifications in cardiovascular disease—An experimental and computational perspective. Epigenetics in Cardiovascular Disease (2021), 113-125. American Geophysical Union (AGU).
Dieterich, Christoph & Völkers, Mirko
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Ythdf2 regulates cardiac remodeling through its m6A-mRNA target transcripts. (2022, 12, 17). American Geophysical Union (AGU).
Kmietczyk, V.; Oelschläger, J.; Varma, E.; Hartl, S.; Konstandin, M.; Marx, A.; Gupta, P.; Loewenthal, Z.; Kamuf-Schenk, V.; Jürgensen, L.; Stroh, C.; Gorska, A.; Jakobi, T.; Frey, N. & Völkers, M.
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Transient Inhibition of Translation Improves Cardiac Function After Ischemia/Reperfusion by Attenuating the Inflammatory Response. Circulation, 150(16), 1248-1267.
Hofmann, Christoph; Serafin, Adrian; Schwerdt, Ole M.; Fischer, Johannes; Sicklinger, Florian; Younesi, Fereshteh S.; Byrne, Nikole J.; Meyer, Ingmar S.; Malovrh, Ellen; Sandmann, Clara; Jürgensen, Lonny; Kamuf-Schenk, Verena; Stroh, Claudia; Löwenthal, Zoe; Finke, Daniel; Boileau, Etienne; Beisaw, Arica; Bugger, Heiko; Rettel, Mandy; ... & Völkers, Mirko
