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

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. • The m 6 A reader IGF2BP1 restricts the induction of human germ cell fate • IGF2BP1 stabilizes m 6 A-modified OTX2 mRNAs to restrict germ line entry • OTX2 interacts with MacroH2A.1 to suppress TFAP2C expression • The m 6 A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C axis regulates human germ cell specification Zhang, Gu, Tong, et al. use human primordial germ cell-like cells induced from ESCs to show that germline entry is restricted via epitranscriptomic regulation of OTX2 by the m 6 A reader IGF2BP1. They demonstrate that an m 6 A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C axis is essential to regulate human germ cell fate.