The m6A mRNA demethylase FTO regulates GnRH secretion in Mn-induced precocious puberty

Xinxin Yang; Zhipeng Qi; Haibo Yang; Jiashuo Li; Yanan Liu; Yanqi Sang; Minghui Li; Xianchao Du; Haiying Wang; Bingchen Liu; Bin Xu; Wei Liu; Zhaofa Xu; Yu Deng

doi:10.1016/j.mce.2021.111523

The m⁶A mRNA demethylase FTO regulates GnRH secretion in Mn-induced precocious puberty

Mol Cell Endocrinol. 2022 Feb 15:542:111523. doi: 10.1016/j.mce.2021.111523. Epub 2021 Nov 27.

Authors

Xinxin Yang¹, Zhipeng Qi², Haibo Yang³, Jiashuo Li⁴, Yanan Liu⁵, Yanqi Sang⁶, Minghui Li⁷, Xianchao Du⁸, Haiying Wang⁹, Bingchen Liu¹⁰, Bin Xu¹¹, Wei Liu¹², Zhaofa Xu¹³, Yu Deng¹⁴

Affiliations

¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China; School of Public Health, Xuzhou Medical University, Xuzhou, 221004, China. Electronic address: xxyang@xzhmu.edu.cn.
² Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: zpqi@cmu.edu.cn.
³ Department of Occupational Diseases, Linyi People's Hospital, Shandong, 276000, China. Electronic address: 13953910708@163.com.
⁴ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: jsli@cmu.edu.cn.
⁵ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: liuyanan@cmu.edu.cn.
⁶ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: yqsang@cmu.edu.cn.
⁷ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: 13214080637@163.com.
⁸ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: duxianchao_cmu@163.com.
⁹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: wanghaiying@cmu.edu.cn.
¹⁰ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: bcliu@cmu.edu.cn.
¹¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: bxu10@cmu.edu.cn.
¹² Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: cmuliuwei@163.com.
¹³ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: zfxu@mail.cmu.edu.cn.
¹⁴ Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, China. Electronic address: dengyu.cmu@163.com.

PMID: 34843901
DOI: 10.1016/j.mce.2021.111523

Abstract

The GABA_A receptor (GABA_AR) plays important roles in the regulation of Mn-induced GnRH secretion in immature female rats. However, the underlying molecular mechanisms remain unknown. Here, we assessed whether FTO and its substrate m⁶A are correlated with GABA_AR expression in GnRH neurons after treatment with Mn in vitro and in vivo. Our study indicated that Mn treatment increased the expression of GnRH mRNA and decreased the levels of GABA_AR protein but had no effect on GABA_AR mRNA. Moreover, Mn upregulated the levels of FTO and inhibited global cellular m⁶A levels and GABA_Aα2 mRNA m⁶A levels. Knockdown of FTO increased the expression of GABA_AR protein and GABA_Aα2 mRNA m⁶A levels. Data from rat models further demonstrate that inhibition of FTO suppressed GABA_AR protein expression in the hypothalamus, causing delayed puberty onset. Collectively, our findings suggest that FTO-dependent m⁶A demethylation plays a critical role in regulating GABA_AR mRNA processing in GnRH neurons.

Keywords: FTO; GABA(A)R; GnRH; Mn; m(6)A.

Publication types

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

MeSH terms

Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
Animals
Female
Gonadotropin-Releasing Hormone* / metabolism
Hypothalamus / metabolism
Neurons / metabolism
Puberty, Precocious* / chemically induced
Puberty, Precocious* / genetics
Puberty, Precocious* / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Rats
Sexual Maturation

Substances

RNA, Messenger
Gonadotropin-Releasing Hormone
Alpha-Ketoglutarate-Dependent Dioxygenase FTO