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Updated: Sep 20, 2025

Generation of Human Primordial Germ Cell-like Cells at the Surface of Embryoid Bodies from Primed-pluripotency Induced Pluripotent Stem Cells
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IGF2BP1 restricts the induction of human primordial germ cell fate in an m6A-dependent manner

Jin Zhang1, Yashi Gu2, Lingling Tong1

  • 1Center 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.

Cell Stem Cell
|May 28, 2025
PubMed

Insights

Epigenetic regulation by N6-methyladenosine (m6A) influences germ cell development. This study reveals an m6A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C pathway that restricts human primordial germ cell-like cell specification.

Area of Science:

  • Developmental biology
  • Epigenetics
  • Stem cell biology

Background:

  • Primordial germ cells (PGCs) are crucial for transmitting genetic information across generations.
  • The role of N6-methyladenosine (m6A) epigenetic modifications in PGC specification is largely unknown.

Purpose of the Study:

  • To investigate the involvement of m6A-mediated epigenetic regulation in human PGC specification.
  • To identify key molecular players in this regulatory pathway.

Main Methods:

  • Utilized a 3D aggregate system to induce human PGC-like cells (hPGCLCs) from embryonic stem cells.
  • Performed gene knockout and overexpression experiments for m6A writers and erasers.
  • Identified m6A reader IGF2BP1 and its downstream targets (OTX2, TFAP2C) and associated histone variant (MacroH2A.1).
  • Validated findings in zebrafish models.

Main Results:

  • Disruption of m6A writers or overexpression of m6A erasers increased hPGCLC induction rates.
  • IGF2BP1 was identified as a key m6A reader restricting hPGCLC fate by stabilizing OTX2 mRNA.
  • OTX2 protein suppresses TFAP2C activity via MacroH2A.1 during germ cell specification.
  • A similar Igf2bp1 role was observed in zebrafish PGC induction.

Conclusions:

  • An m6A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C signaling axis restricts human germ cell fate specification.
  • This pathway highlights the importance of m6A epitranscriptomics in early germ cell development.

Keywords:
IGF2BP1MacroH2A.1OTX2PGC restrictorsTFAP2Cm(6)A modificationprimordial germ cells

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