UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells

Ambre Bender, Marion Morel, Michael Dumas, Muriel Klopfenstein, Naël Osmani, Maxim V. C. Greenberg, Déborah Bourc’his, Norbert B. Ghyselinck and Michael Weber ()
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Ambre Bender: Université de Strasbourg
Marion Morel: Université de Strasbourg
Michael Dumas: Université de Strasbourg
Muriel Klopfenstein: BP-10142
Naël Osmani: Université de Strasbourg
Maxim V. C. Greenberg: INSERM U934
Déborah Bourc’his: INSERM U934
Norbert B. Ghyselinck: BP-10142
Michael Weber: Université de Strasbourg

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61954-0

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