Dataset Information

METTL3-mediated mRNA N⁶-methyladenosine is required for oocyte and follicle development in mice.

ABSTRACT: Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological process requires precise gene regulation. The most abundant modification of mRNA, N⁶-methyladenosine (m⁶A), is involved in many RNA metabolism processes, including RNA splicing, translation, stability, and degradation. Here, we report that m⁶A plays essential roles during oocyte and follicle development. Oocyte-specific inactivation of the key m⁶A methyltransferase Mettl3 with Gdf9-Cre caused DNA damage accumulation in oocytes, defective follicle development, and abnormal ovulation. Mechanistically, combined RNA-seq and m⁶A methylated RNA immunoprecipitation sequencing (MeRIP-seq) data from oocytes revealed, that we found METTL3 targets Itsn2 for m⁶A modification and then enhances its stability to influence the oocytes meiosis. Taken together, our findings highlight the crucial roles of mRNA m⁶A modification in follicle development and coordination of RNA stabilization during oocyte growth.

SUBMITTER: Mu H

PROVIDER: S-EPMC8542036 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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METTL3-mediated mRNA N6-methyladenosine is required for oocyte and follicle development in mice.

Mu Haiyuan H Zhang Ting T Yang Ying Y Zhang Danru D Gao Jie J Li Junhong J Yue Liang L Gao Dengfeng D Shi Bingbo B Han Yue Y Zhong Liang L Chen Xinze X Wang Zhen-Bo ZB Lin Zhen Z Tong Ming-Han MH Sun Qing-Yuan QY Yang Yun-Gui YG Han Jianyong J

Cell death & disease 20211023 11

Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological process requires precise gene regulation. The most abundant modification of mRNA, N6-methyladenosine (m6A), is involved in many RNA metabolism processes, including RNA splicing, translation, stability, and degradation. Here, we report that m6A plays essential roles during oocyte and follicle develo ...[more]

PMID: 34689175

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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

METTL3-mediated mRNA N⁶-methyladenosine is required for oocyte and follicle development in mice.

Publications

METTL3-mediated mRNA N<sup>6</sup>-methyladenosine is required for oocyte and follicle development in mice.

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