Wu Yunqiang, Xu Bo, Peng Yonglin, Lin Sang, Du Wenfei, Liu Ruiqi, Zhang Shu, Wu Ji, Zou Kang, Zhao Xiaodong
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Clin Epigenetics. 2025 May 27;17(1):84. doi: 10.1186/s13148-025-01890-4.
Germline stem cells are critical for sustaining fertility by balancing self-renewal and differentiation, and are regulated by genetic and epigenetic programs. Although extensively investigated, the rare female germline stem cells (FGSCs) in mammalian ovaries hinder their application in regenerative medicine. The N-methyladenosine (mA) reader YTHDF2 is required for female germ cell competence. However, the mechanistic underpinnings of how YTHDF2 regulates FGSC proliferation remain elusive.
Here, we show that knockout of Ythdf2 enhances FGSC proliferation in vitro. YTHDF2 binds mA-modified Ets1 mRNA and facilitates its degradation in an mA-dependent manner. ETS1 functions as a key downstream effector of YTHDF2, as suppression of ETS1 expression partially reverses the Ythdf2-KO-induced phenotype. Additionally, we demonstrate that YTHDF2/ETS1 axis participates in regulating FGSC proliferation by modulation of proliferation-related gene expression. Moreover, histone lactylation modification H3K18la activates the expression of YTHDF2 in FGSCs.
Overall, our study reveals that YTHDF2 intrinsically restrains mouse FGSC proliferation and provides a potential strategy to increase FGSC abundance for its potential clinical application.
生殖系干细胞对于通过平衡自我更新和分化来维持生育能力至关重要，并受遗传和表观遗传程序调控。尽管已进行了广泛研究，但哺乳动物卵巢中罕见的雌性生殖系干细胞（FGSC）阻碍了它们在再生医学中的应用。N-甲基腺苷（mA）阅读器YTHDF2是雌性生殖细胞能力所必需的。然而，YTHDF2如何调节FGSC增殖的机制仍不清楚。
在这里，我们表明敲除Ythdf2可增强体外FGSC的增殖。YTHDF2结合mA修饰的Ets1 mRNA，并以mA依赖的方式促进其降解。ETS1作为YTHDF2的关键下游效应物，因为抑制ETS1表达可部分逆转Ythdf2基因敲除诱导的表型。此外，我们证明YTHDF2/ETS1轴通过调节增殖相关基因的表达参与调节FGSC增殖。此外，组蛋白乳酰化修饰H3K18la激活FGSC中YTHDF2的表达。
总体而言，我们的研究表明YTHDF2本质上抑制小鼠FGSC增殖，并为增加FGSC丰度以用于其潜在临床应用提供了一种潜在策略。
