胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）以N6-甲基腺苷（mA）依赖的方式限制人类原始生殖细胞命运的诱导。

IGF2BP1 restricts the induction of human primordial germ cell fate in an mA-dependent manner.

作者信息

Zhang Jin, Gu Yashi, Tong Lingling, Feng Boshi, Dong Shenghua, Shao Qizhe, Chen Yanxi, Tu Huanchang, Wang Ziqi, Wang Yueqi, Li Xiang, Yu Honglin, Lin Ziying, Wang Xueting, Li Zhenfu, Ai Zhipeng, Xiang Yangquan, Jiang Zhiwei, Jin Zixin, Li Zhengyi, Chen Yuxin, Shen Zuolin, Huang Chenyang, Liu Jianzhao, Liu Jian, Xu Pengfei, Yu You, Xia Peng, Liang Hongqing, Huang Huilin, Chen Di

机构信息

Center for Regeneration and Cell Therapy of Zhejiang University, University of Edinburgh Institute (ZJU-UoE Institute), Center for Reproductive Medicine of The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Edinburgh Medical School, Biomedical Sciences, College of Medicine and Veterinary Medicine, the University of Edinburgh, Edinburgh, UK.

出版信息

Cell Stem Cell. 2025 Jul 3;32(7):1122-1138.e13. doi: 10.1016/j.stem.2025.05.001. Epub 2025 May 27.

DOI:10.1016/j.stem.2025.05.001

PMID:40436019

Abstract

Primordial germ cells (PGCs) are specified early during embryogenesis and establish the germ cell lineage for transmitting genetic and epigenetic information from parents to offspring. However, whether N-methyladenosine (mA)-mediated epigenetic regulation is involved in the specification of PGCs remains elusive. In this study, we report that a knockout of mA writers or overexpression of mA erasers leads to an increased percentage of human PGC-like cells (hPGCLCs) induced from embryonic stem cells using a 3D aggregate system. We identify the mA reader IGF2BP1 as the key factor for restricting hPGCLC fate induction by stabilizing OTX2 mRNAs in an mA-dependent manner. In turn, OTX2 protein suppresses the function of TFAP2C via histone variant MacroH2A.1 during germ cell lineage specification. We also observe a similar role of Igf2bp1 in zebrafish in the induction of PGC fate. In summary, we identify an mA-IGF2BP1-OTX2-MacroH2A.1-TFAP2C signaling axis that restricts the specification of human germ cell fate.

摘要

原始生殖细胞（PGCs）在胚胎发育早期就已特化，并建立生殖细胞谱系，用于将遗传和表观遗传信息从亲代传递给子代。然而，N-甲基腺苷（mA）介导的表观遗传调控是否参与PGCs的特化仍不清楚。在本研究中，我们报道使用三维聚集体系统敲除mA写入器或过表达mA擦除器会导致从胚胎干细胞诱导产生的人类原始生殖细胞样细胞（hPGCLCs）百分比增加。我们鉴定出mA阅读器IGF2BP1是通过以mA依赖的方式稳定OTX2 mRNA来限制hPGCLC命运诱导的关键因子。反过来，在生殖细胞谱系特化过程中，OTX2蛋白通过组蛋白变体MacroH2A.1抑制TFAP2C的功能。我们还观察到Igf2bp1在斑马鱼中对PGC命运诱导具有类似作用。总之，我们鉴定出一个mA-IGF2BP1-OTX2-MacroH2A.1-TFAP2C信号轴，该信号轴限制人类生殖细胞命运的特化。