IGF2BP1 restricts the induction of human primordial germ cell fate in an m6A-dependent manner

作者：Jin Zhang, Yashi Gu, Lingling Tong, Boshi Feng, Shenghua Dong, Qizhe Shao, Yanxi Chen, Huanchang Tu, Ziqi Wang, Yueqi Wang, Xiang Li, Honglin Yu, Ziying Lin, Xueting Wang, Zhenfu Li, Zhipeng Ai, Yangquan Xiang, Zhiwei Jiang, Zixin Jin, Zhengyi Li, Yuxin Chen, Zuolin Shen, Chenyang Huang, Jianzhao Liu, Jian Liu, Peng‐Fei Xu, Yu You, Peng Xia, Hongqing Liang, Huilin Huang, Di Chen · 发表于：Cell stem cell · 年份：2025 · DOI：10.1016/j.stem.2025.05.001 · 被引用次数：8 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Viral-associated cancers and disorders

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 6 -methyladenosine (m 6 A)-mediated epigenetic regulation is involved in the specification of PGCs remains elusive. In this study, we report that a knockout of m 6 A writers or overexpression of m 6 A 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 m 6 A reader IGF2BP1 as the key factor for restricting hPGCLC fate induction by stabilizing OTX2 mRNAs in an m 6 A-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 m 6 A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C signaling axis that restricts the specification of human germ cell fate.