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The m 6 A mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy.

Circulation 2018 November 29
BACKGROUND: m6 A methylation is the most prevalent internal post-transcriptional modification on mammalian mRNA. The role of m6 A mRNA methylation in the heart is not known.

METHODS: To determine the role of m6 A methylation in the heart we isolated primary cardiomyocytes and performed m6 A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6 A levels in cardiomyocytes by manipulating the levels of the m6 A RNA methylase METTL3 both in culture and in vivo. We generated cardiac-restricted gain and loss of function mouse models to allow assessment of the METTL3-m6 A pathway in cardiac homeostasis and function.

RESULTS: We measured the level of m6 A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6 A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6 A 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, while increased expression of the m6 A 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 maintenance of cardiac homeostasis.

CONCLUSIONS: Our study identified METTL3-mediated methylation of mRNA on N6-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6 A RNA methylation results in compensated cardiac hypertrophy whereas diminished m6 A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.

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