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UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells

Author

Listed:
  • Ambre Bender

    (Université de Strasbourg
    300 Bd Sébastien Brant)

  • Marion Morel

    (Université de Strasbourg
    300 Bd Sébastien Brant)

  • Michael Dumas

    (Université de Strasbourg
    300 Bd Sébastien Brant)

  • Muriel Klopfenstein

    (BP-10142)

  • Naël Osmani

    (Université de Strasbourg
    INSERM UMR_S1109
    Fédération de Médecine Translationnelle de Strasbourg (FMTS)
    Equipe Labellisée Ligue Contre le Cancer)

  • Maxim V. C. Greenberg

    (INSERM U934
    Institut Jacques Monod)

  • Déborah Bourc’his

    (INSERM U934)

  • Norbert B. Ghyselinck

    (BP-10142)

  • Michael Weber

    (Université de Strasbourg
    300 Bd Sébastien Brant)

Abstract

In mammals, primordial germ cells (PGCs) undergo global erasure of DNA methylation with delayed demethylation of germline genes and selective retention of DNA methylation at evolutionarily young retrotransposons. However, the molecular mechanisms of persistent DNA methylation in PGCs remain unclear. Here we report that resistance to DNA methylation reprogramming in PGCs requires UHRF2, the paralog of the DNMT1 cofactor UHRF1. PGCs from Uhrf2 knock-out mice show loss of retrotransposon DNA methylation, while DNA methylation is unaffected in somatic cells. This is not associated with changes in the expression of retrotransposons in E13.5 PGCs, indicating that other mechanisms compensate for retrotransposon control at this stage. Furthermore, Uhrf2-deficient PGCs show precocious demethylation of germline genes and overexpress meiotic genes in females. Subsequently, Uhrf2-deficient mice show impaired oocyte development and female-specific reduced fertility, as well as incomplete remethylation of retrotransposons during spermatogenesis. These findings reveal a crucial function for the UHRF1 paralog UHRF2 in controlling DNA methylation in the germline.

Suggested Citation

  • Ambre Bender & Marion Morel & Michael Dumas & Muriel Klopfenstein & Naël Osmani & Maxim V. C. Greenberg & Déborah Bourc’his & Norbert B. Ghyselinck & Michael Weber, 2025. "UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61954-0
    DOI: 10.1038/s41467-025-61954-0
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