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; Yimin Zhu

doi:10.1038/s41467-023-42302-6

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

Nat Commun. 2023 Oct 17;14(1):6532. doi: 10.1038/s41467-023-42302-6.

Authors

Long Bai^#^{1

2

3}, Yu Xiang^#^{4

5

6}, Minyue Tang^#^{4

5

6}, Shuangying Liu^{4

5

6}, Qingqing Chen^{4

5

6}, Qichao Chen^{4

5

6}, Min Zhang^{4

5

6}, Shan Wan^{4

5

6}, Yimiao Sang^{4

5

6}, Qingfang Li^{4

5

6}, Sisi Wang^{4

5

6}, Zhekun Li^{4

5

6}, Yang Song^{4

5

6}, Xiaoling Hu^{4

5

6}, Luna Mao^{4

5

6}, Guofang Feng^{4

5

6}, Long Cui^{4

5

6}, Yinghui Ye^{4

5

6}, Yimin Zhu^{7

8

9}

Affiliations

¹ Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China. bailong0375@zju.edu.cn.
² Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. bailong0375@zju.edu.cn.
³ Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. bailong0375@zju.edu.cn.
⁴ Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China.
⁵ Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
⁶ Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
⁷ Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China. zhuyim@zju.edu.cn.
⁸ Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. zhuyim@zju.edu.cn.
⁹ Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. zhuyim@zju.edu.cn.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AlkB Homolog 5, RNA Demethylase / genetics
AlkB Homolog 5, RNA Demethylase / metabolism
Female
Humans
Meiosis / genetics
Methylation
Oocytes* / metabolism
Oogenesis* / genetics
Oogenesis* / physiology
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

AlkB Homolog 5, RNA Demethylase
ALKBH5 protein, human
IGF2BP2 protein, human
RNA, Messenger
RNA-Binding Proteins