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

Long Bai (), Yu Xiang, Minyue Tang, Shuangying Liu, Qingqing Chen, Qichao Chen, Min Zhang, Shan Wan, Yimiao Sang, Qingfang Li, Sisi Wang, Zhekun Li, Yang Song, Xiaoling Hu, Luna Mao, Guofang Feng, Long Cui, Yinghui Ye and Yimin Zhu ()
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Long Bai: School of Medicine, Zhejiang University
Yu Xiang: School of Medicine, Zhejiang University
Minyue Tang: School of Medicine, Zhejiang University
Shuangying Liu: School of Medicine, Zhejiang University
Qingqing Chen: School of Medicine, Zhejiang University
Qichao Chen: School of Medicine, Zhejiang University
Min Zhang: School of Medicine, Zhejiang University
Shan Wan: School of Medicine, Zhejiang University
Yimiao Sang: School of Medicine, Zhejiang University
Qingfang Li: School of Medicine, Zhejiang University
Sisi Wang: School of Medicine, Zhejiang University
Zhekun Li: School of Medicine, Zhejiang University
Yang Song: School of Medicine, Zhejiang University
Xiaoling Hu: School of Medicine, Zhejiang University
Luna Mao: School of Medicine, Zhejiang University
Guofang Feng: School of Medicine, Zhejiang University
Long Cui: School of Medicine, Zhejiang University
Yinghui Ye: School of Medicine, Zhejiang University
Yimin Zhu: School of Medicine, Zhejiang University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42302-6

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