Year: 2025
Type: article
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.
Source: Nature Communications
Institutions: Centre National de la Recherche Scientifique, Biotechnologie et Signalisation Cellulaire, Université de Strasbourg, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, La Ligue Contre le Cancer, Université Paris Cité, Université Paris Sciences et Lettres, Institut Jacques Monod, Institut Curie
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1587956506, G164444715, G1800105685, Par-delà les frontières, l'Université de Strasbourg, G2255650664, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique, G2694206344, Façonner les talents en formation et en recherche à l'Université de Strasbourg, G3357951378, Elucidating the biological function of UHRF2 in mammals, G399734812, G471331628, G5296751580, G6276897512, G6803667113, G6888366887, G7080048889, G7240651115, G7786862643, Identification of novel functions and regulators of DNA methylation in mammals, G8144793849, DNMT3C, a new DNA methylation player in transposon control and mammalian fertility
OpenAlex ID: W4413094573