Dataset Information

ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N ⁶-methyladenosine methylation.

ABSTRACT: N⁶-methyladenosine (m⁶A) maintains maternal RNA stability in oocytes. One regulator of m⁶A, ALKBH5, reverses m⁶A deposition and is essential in RNA metabolism. However, the specific role of ALKBH5 in oocyte maturation remains elusive. Here, we show that Alkbh5 depletion causes a wide range of defects in oocyte meiosis and results in female infertility. Temporal profiling of the maternal transcriptomes revealed striking RNA accumulation in Alkbh5^-/- oocytes during meiotic maturation. Analysis of m⁶A dynamics demonstrated that ALKBH5-mediated m⁶A demethylation ensures the timely degradation of maternal RNAs, which is severely disrupted following Alkbh5^-/- depletion. A distinct subset of transcripts with persistent m⁶A peaks are recognized by the m⁶A reader IGF2BP2 and thus remain stabilized, resulting in impaired RNA clearance. Additionally, reducing IGF2BP2 in Alkbh5-depleted oocytes partially rescued these defects. Overall, this work identifies ALKBH5 as a key determinant of oocyte quality and unveil the facilitating role of ALKBH5-mediated m⁶A removal in maternal RNA decay.

SUBMITTER: Bai L

PROVIDER: S-EPMC10582257 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N 6-methyladenosine methylation.

Bai Long L Xiang Yu Y Tang Minyue M Liu Shuangying S Chen Qingqing Q Chen Qichao Q Zhang Min M Wan Shan S Sang Yimiao Y Li Qingfang Q Wang Sisi S Li Zhekun Z Song Yang Y Hu Xiaoling X Mao Luna L Feng Guofang G Cui Long L Ye Yinghui Y Zhu Yimin Y

Nature communications 20231017 1

N6-methyladenosine (m6A) maintains maternal RNA stability in oocytes. One regulator of m6A, ALKBH5, reverses m6A deposition and is essential in RNA metabolism. However, the specific role of ALKBH5 in oocyte maturation remains elusive. Here, we show that Alkbh5 depletion causes a wide range of defects in oocyte meiosis and results in female infertility. Temporal profiling of the maternal transcriptomes revealed striking RNA accumulation in Alkbh5-/ ...[more]

PMID: 37848452

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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

ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N ⁶-methyladenosine methylation.

Publications

ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N <sup>6</sup>-methyladenosine methylation.

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