The N-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy

Lisa E. Dorn, Lior Lasman, Jing Chen, Xianyao Xu, Thomas J. Hund, Mario Medvedovic, Jacob H. Hanna, Jop H. Van Berlo, Federica Accornero

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

N-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known. Methods: To determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function. Results: We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis. Conclusions: Our study identified METTL3-mediated methylation of mRNA on N-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.

Original languageEnglish (US)
Pages (from-to)533-545
Number of pages13
JournalCirculation
Volume139
Issue number4
DOIs
StatePublished - Jan 22 2019

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (HL112852 and HL130072 to Dr van Berlo, HL121284 and HL136951 to Dr Accornero, and HL134616 to L.E. Dorn); the American Heart Association (AHA 17IRG33460198 to Dr Accornero); The Israel Science Foundation (355/17 and 107/14), the Flight Attendant Medical Research Council, the New York Stem

Funding Information:
Cell Foundation, and the European Research Council Consolidator Grant Cell-Naivety (to Dr Hanna); and The United States-Israel Binational Science Foundation (2017094 to Drs Accornero and Hanna).

Publisher Copyright:
© 2018 American Heart Association, Inc.

Keywords

  • RNA processing
  • gene expression profiling
  • hypertrophy
  • mice
  • post-transcriptional
  • transgenic

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