Department of endocrinology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, 200062, Shanghai, China.
Commun Biol. 2023 Dec 21;6(1):1297. doi: 10.1038/s42003-023-05677-2.
N-methyladenosine (mA) plays a crucial role in the development and functional homeostasis of the central nervous system. The fat mass and obesity-associated (FTO) gene, which is highly expressed in the hypothalamus, is closely related to female pubertal development. In this study, we found that mA methylation decreased in the hypothalamus gradually with puberty and decreased in female rats with precocious puberty. FTO expression was increased at the same time. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the mA methylation of PLCβ, a key enzyme of the Ca signalling pathway, was decreased significantly in the hypothalamus in precocious rats. Upregulating FTO increased PLCβ3 expression and activated the Ca signalling pathway, which promoted GnRH expression. Dual-luciferase reporter and MeRIP-qPCR assays confirmed that FTO regulated mA demethylation of PLCβ and promoted PLCβ expression. Upon overexpressing FTO in the hypothalamic arcuate nucleus (ARC) in female rats, we observed advanced puberty onset. Meanwhile, PLCβ and GnRH expression in the hypothalamus increased significantly, and the Ca signalling pathway was activated. Our study demonstrates that FTO enhances GnRH expression, which promotes puberty onset, by regulating mA demethylation of PLCβ3 and activating the Ca signalling pathway.
N6-甲基腺苷（mA）在中枢神经系统的发育和功能动态平衡中起着至关重要的作用。脂肪质量和肥胖相关（FTO）基因在脑下垂体中高度表达，与女性青春期发育密切相关。在这项研究中，我们发现，mA 的甲基化随着青春期逐渐减少，并且在性早熟的雌性大鼠中减少。同时 FTO 的表达增加。甲基化 RNA 免疫沉淀测序（MeRIP-seq）显示，在性早熟大鼠的脑下垂体中，Ca 信号通路的关键酶 PLCβ 的 mA 甲基化显著降低。上调 FTO 增加了 PLCβ3 的表达并激活了 Ca 信号通路，从而促进了 GnRH 的表达。双荧光素酶报告和 MeRIP-qPCR 检测证实，FTO 调节 PLCβ 的 mA 去甲基化并促进 PLCβ 的表达。在雌性大鼠的下丘脑弓状核（ARC）中过度表达 FTO 后，我们观察到青春期提前开始。同时，下丘脑的 PLCβ 和 GnRH 表达显著增加，Ca 信号通路被激活。我们的研究表明，FTO 通过调节 PLCβ3 的 mA 去甲基化并激活 Ca 信号通路，增强 GnRH 的表达，从而促进青春期的开始。
