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<sup>6</sup>-methyladenosine (m<sup>6</sup>A)-mediated epigenetic regulation is involved in the specification of PGCs remains elusive. In this study, we report that a knockout of m<sup>6</sup>A writers or overexpression of m<sup>6</sup>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<sup>6</sup>A reader IGF2BP1 as the key factor for restricting hPGCLC fate induction by stabilizing OTX2 mRNAs in an m<sup>6</sup>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<sup>6</sup>A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C signaling axis that restricts the specification of human germ cell fate.
Authors
- Jian Liu (ORCID: https://orcid.org/0000-0003-3101-7553)
- Jianzhao Liu (ORCID: https://orcid.org/0000-0001-9465-6075)
- Ziying Lin (ORCID: https://orcid.org/0000-0002-9789-8528)
- Yangquan Xiang (ORCID: https://orcid.org/0000-0002-1368-4929)
- Qizhe Shao (ORCID: https://orcid.org/0009-0001-8572-7019)
- Chenyang Huang (ORCID: https://orcid.org/0000-0002-1956-6229)
- Zhi‐Liang Shen (ORCID: https://orcid.org/0000-0002-3365-9288)
- Peng‐Fei Xu (ORCID: https://orcid.org/0000-0002-7318-8548)
- Shenghua Dong (ORCID: https://orcid.org/0000-0001-8490-8144)
- Huilin Huang (ORCID: https://orcid.org/0000-0003-2608-572X)
- Hongqing Liang (ORCID: https://orcid.org/0000-0002-5494-2197)
- Zhiwei Jiang (ORCID: https://orcid.org/0000-0001-8203-6151)
- Yuxin Chen (ORCID: https://orcid.org/0000-0003-0658-7562)
- Zhenfu Li
- Yu You (ORCID: https://orcid.org/0000-0002-5273-1740)
- Xiang Li (ORCID: https://orcid.org/0000-0003-2964-8639)
- Ziqi Wang (ORCID: https://orcid.org/0009-0007-6701-5177)
- Zhengyi Li (ORCID: https://orcid.org/0000-0002-0370-7912)
- Xueting Wang (ORCID: https://orcid.org/0000-0003-3152-8804)
- Yueqi Wang (ORCID: https://orcid.org/0000-0002-3719-465X)
- Yanxi Chen (ORCID: https://orcid.org/0009-0004-7427-1820)
- Jin Zhang (ORCID: https://orcid.org/0000-0003-2460-0396)
- Honglin Yu
- Peng Xia (ORCID: https://orcid.org/0000-0002-5419-7756)
- Lingling Tong (ORCID: https://orcid.org/0000-0001-9206-0155)
- Yashi Gu
- Zixin Jin
- Baijie Feng (ORCID: https://orcid.org/0009-0002-1549-6080)
- Huanchang Tu
- Di Chen (ORCID: https://orcid.org/0009-0000-3863-7566)
- Zhipeng Ai
Institutions
- Zhejiang International Studies University (CN)
- Sun Yat-sen University (CN)
- Edinburgh College (GB)
- Medical Research Scotland (GB)
- Zhejiang Cancer Hospital (CN)
- Women's Hospital, School of Medicine, Zhejiang University (CN)
- Sun Yat-sen University Cancer Center (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University-University of Edinburgh Institute (CN)
- Zhejiang University (CN)
- University of Edinburgh (GB)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1016/j.stem.2025.05.001
- Citations
- 6
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Zhejiang Province