Dataset Information

N⁶-Methyladenosine METTL3 Modulates the Proliferation and Apoptosis of Lens Epithelial Cells in Diabetic Cataract.

ABSTRACT: N⁶-methyladenosine (m⁶A) is the most prevalent eukaryotic messenger RNA modification. Diabetic cataract (DC) is caused by high glucose (HG) in diabetes mellitus. However, the regulatory mechanism of m⁶A in the DC pathogenesis is poorly understood. In present research, we performed the m⁶A-RNA immunoprecipitation sequencing (MeRIP-Seq) analysis and detected the m⁶A modification profile in the HG- or normal glucose (NG)-induced human lens epithelial cells (HLECs). Results revealed that methyltransferase-like 3 (METTL3) was upregulated in the DC tissue specimens and HG-induced HLECs. Besides, total m⁶A modification level was higher in the HG-induced HLECs. Functionally, METTL3 knockdown promoted the proliferation and repressed the apoptosis of HLECs induced by HG. MeRIP-Seq analysis revealed that ICAM-1 might act as the target of METTL3. Mechanistically, METTL3 targets the 3' UTR of ICAM-1 to stabilize mRNA stability. In conclusion, this research identified the regulation of METTL3 in the HG-induced HLECs, providing a potential insight of the m⁶A modification for DC.

SUBMITTER: Yang J

PROVIDER: S-EPMC7066033 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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N6-Methyladenosine METTL3 Modulates the Proliferation and Apoptosis of Lens Epithelial Cells in Diabetic Cataract.

Yang Jun J Liu Jingshu J Zhao Shaozhen S Tian Fang F

Molecular therapy. Nucleic acids 20200211

N6-methyladenosine (m6A) is the most prevalent eukaryotic messenger RNA modification. Diabetic cataract (DC) is caused by high glucose (HG) in diabetes mellitus. However, the regulatory mechanism of m6A in the DC pathogenesis is poorly understood. In present research, we performed the m6A-RNA immunoprecipitation sequencing (MeRIP-Seq) analysis and detected the m6A modification profile in the HG- or normal glucose (NG)-induced human lens epit ...[more]

PMID: 32163892

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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.

Dataset Information

N⁶-Methyladenosine METTL3 Modulates the Proliferation and Apoptosis of Lens Epithelial Cells in Diabetic Cataract.

Publications

N<sup>6</sup>-Methyladenosine METTL3 Modulates the Proliferation and Apoptosis of Lens Epithelial Cells in Diabetic Cataract.

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