UHRF2 mediates resistance to DNA methylation reprogramming in primordial germ cells

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-08-09 DOI:10.1038/s41467-025-61954-0

Ambre Bender, Marion Morel, Michael Dumas, Muriel Klopfenstein, Naël Osmani, Maxim V. C. Greenberg, Déborah Bourc’his, Norbert B. Ghyselinck, Michael Weber

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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.

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UHRF2介导原始生殖细胞对DNA甲基化重编程的抗性

在哺乳动物中，原始生殖细胞（PGCs）通过生殖系基因的延迟去甲基化和进化上年轻的反转录转座子的DNA甲基化选择性保留来进行DNA甲基化的全局清除。然而，PGCs中持续DNA甲基化的分子机制尚不清楚。在这里，我们报告了PGCs对DNA甲基化重编程的抗性需要UHRF2，即DNMT1辅助因子UHRF1的类似物。Uhrf2敲除小鼠的PGCs显示逆转录转座子DNA甲基化缺失，而体细胞的DNA甲基化不受影响。这与E13.5 PGCs中反转录转座子表达的变化无关，表明在这一阶段，其他机制补偿了反转录转座子的控制。此外，缺乏uhrf2的PGCs在雌性中表现出生殖系基因的过早去甲基化和减数分裂基因的过度表达。随后，uhrf2缺陷小鼠表现出卵母细胞发育受损和雌性特异性生育能力下降，以及精子发生过程中反转录转座子的不完全再甲基化。这些发现揭示了UHRF1平行基因UHRF2在控制种系DNA甲基化中的关键功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.