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Role of METTL3-Dependent N⁶-Methyladenosine mRNA Modification in the Promotion of Angiogenesis.

ABSTRACT: Epigenetic alterations occur in many physiological and pathological processes. N⁶-methyladenosine (m⁶A) modification is the most prevalent modification in eukaryotic mRNAs. However, the role of m⁶A modification in pathological angiogenesis remains elusive. In this study, we showed that the level of m⁶A modification was significantly upregulated in endothelial cells and mouse retinas following hypoxic stress, which was caused by increased METTL3 levels. METTL3 silencing or METTL3 overexpression altered endothelial cell viability, proliferation, migration, and tube formation in vitro. METTL3 knockout in vivo decreased avascular area and pathological neovascular tufts in an oxygen-induced retinopathy model and inhibited alkali burn-induced corneal neovascularization. Mechanistically, METTL3 exerted its angiogenic role by regulating Wnt signaling through the m⁶A modification of target genes (e.g., LRP6 and dishevelled 1 [DVL1]). METTL3 enhanced the translation of LRP6 and DVL1 in an YTH m⁶A RNA-binding protein 1 (YTHDF1)-dependent manner. Collectively, this study suggests that METTL3-mediated m⁶A modification is an important hypoxic stress-response mechanism. The targeting of m⁶A through its writer enzyme METTL3 is a promising strategy for the treatment of angiogenic diseases.

SUBMITTER: Yao MD

PROVIDER: S-EPMC7545007 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundN6-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.MethodsTo 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.ResultsWe 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.ConclusionsOur 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 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.

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Role of METTL3-Dependent N⁶-Methyladenosine mRNA Modification in the Promotion of Angiogenesis.

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Dataset Information

Role of METTL3-Dependent N6-Methyladenosine mRNA Modification in the Promotion of Angiogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Role of METTL3-Dependent N⁶-Methyladenosine mRNA Modification in the Promotion of Angiogenesis.