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

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; Pengfei Xu; You Yu; Peng Xia; Hongqing Liang; Huilin Huang; Di Chen

doi:10.1016/j.stem.2025.05.001

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

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

Authors

Jin Zhang¹, Yashi Gu², Lingling Tong¹, Boshi Feng¹, Shenghua Dong³, Qizhe Shao², Yanxi Chen¹, Huanchang Tu¹, Ziqi Wang¹, Yueqi Wang¹, Xiang Li¹, Honglin Yu², Ziying Lin⁴, Xueting Wang⁴, Zhenfu Li⁵, Zhipeng Ai⁶, Yangquan Xiang⁶, Zhiwei Jiang⁷, Zixin Jin⁸, Zhengyi Li¹, Yuxin Chen¹, Zuolin Shen⁷, Chenyang Huang⁹, Jianzhao Liu⁹, Jian Liu¹⁰, Pengfei Xu⁸, You Yu⁷, Peng Xia⁴, Hongqing Liang¹¹, Huilin Huang¹², Di Chen¹³

Affiliations

¹ 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.
² 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.
³ State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
⁴ Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
⁵ Edinburgh Medical School, Biomedical Sciences, College of Medicine and Veterinary Medicine, the University of Edinburgh, Edinburgh, UK.
⁶ Division of Human Reproduction and Developmental Genetics, Women's Hospital, and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
⁷ Department for Cardiology of The Second Affiliated Hospital, Center for Infection Immunity, Cancer of Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
⁸ Center for Genetic Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, Zhejiang University, Yiwu 322000, China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
⁹ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China.
¹⁰ Department for Cardiology of The Second Affiliated Hospital, Center for Infection Immunity, Cancer of Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China; Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, Zhejiang 314400, China.
¹¹ Division of Human Reproduction and Developmental Genetics, Women's Hospital, and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China; Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China. Electronic address: lianghongqing@zju.edu.cn.
¹² State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China. Electronic address: huanghl1@sysucc.org.cn.
¹³ 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; Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, Zhejiang 314400, China; State Key Laboratory of Biobased Transportation Fuel Technology, Haining, Zhejiang 314400, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China. Electronic address: dichen@intl.zju.edu.cn.

PMID: 40436019
DOI: 10.1016/j.stem.2025.05.001

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 N⁶-methyladenosine (m⁶A)-mediated epigenetic regulation is involved in the specification of PGCs remains elusive. In this study, we report that a knockout of m⁶A writers or overexpression of m⁶A 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 m⁶A reader IGF2BP1 as the key factor for restricting hPGCLC fate induction by stabilizing OTX2 mRNAs in an m⁶A-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 m⁶A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C signaling axis that restricts the specification of human germ cell fate.

Keywords: IGF2BP1; MacroH2A.1; OTX2; PGC restrictors; TFAP2C; m(6)A modification; primordial germ cells.

MeSH terms

Adenosine* / analogs & derivatives
Adenosine* / metabolism
Animals
Cell Differentiation
Cell Lineage
Germ Cells* / cytology
Germ Cells* / metabolism
Histones / metabolism
Humans
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Transcription Factor AP-2 / metabolism
Zebrafish

Substances

RNA-Binding Proteins
IGF2BP1 protein, human
N-methyladenosine
Adenosine
Histones
Transcription Factor AP-2
TFAP2C protein, human