The histone H3 lysine 36 demethylase KDM2A/FBXL11 controls Polycomb-mediated gene repression and germ cell development in male mice

Michael T. Bocker, Grigorios Fanourgakis, Kristie Wetzel, Pavel A. Komarov, Hélène Royo, Alexia Rohmer, Sunwoo Chun, Ching-Yeu Liang, Hubertus Kohler, Taiping Chen, Xiaohong Mao, Mark A. Labow, Reginald A. Valdez, Michael B. Stadler, Dirk G. Rooij, Paola Capodieci, John Tallarico, Antoine H. F. M. Peters () and Thomas B. Nicholson ()
Additional contact information
Michael T. Bocker: Novartis Biomedical Research
Grigorios Fanourgakis: Friedrich Miescher Institute for Biomedical Research (FMI)
Kristie Wetzel: Novartis Biomedical Research
Pavel A. Komarov: Friedrich Miescher Institute for Biomedical Research (FMI)
Hélène Royo: Friedrich Miescher Institute for Biomedical Research (FMI)
Alexia Rohmer: Friedrich Miescher Institute for Biomedical Research (FMI)
Sunwoo Chun: Friedrich Miescher Institute for Biomedical Research (FMI)
Ching-Yeu Liang: Friedrich Miescher Institute for Biomedical Research (FMI)
Hubertus Kohler: Friedrich Miescher Institute for Biomedical Research (FMI)
Taiping Chen: Novartis Biomedical Research
Xiaohong Mao: Novartis Biomedical Research
Mark A. Labow: Novartis Biomedical Research
Reginald A. Valdez: Novartis Biomedical Research
Michael B. Stadler: Friedrich Miescher Institute for Biomedical Research (FMI)
Dirk G. Rooij: Utrecht University
Paola Capodieci: Novartis Biomedical Research
John Tallarico: Novartis Biomedical Research
Antoine H. F. M. Peters: Friedrich Miescher Institute for Biomedical Research (FMI)
Thomas B. Nicholson: Novartis Biomedical Research

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a-dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters in Kdm2a-deficient spermatogonia. KDM2A is required for Polycomb-mediated repression as shown by increased H3K36me2 and reduced H3K27me3 promoter occupancies and failed gene repression in Kdm2a deficient differentiating spermatogonia. Loss of Kdm2a in spermatocytes disrupts progression through meiotic prophase, as evidenced by impaired completion of chromosome synapsis and processing of meiotic double-strand breaks (DSBs), by altered chromatin states and by an impairment of X-linked gene repression. Our study thus identifies critical roles for KDM2A in coordinating gene expression programs during spermatogonial differentiation and meiosis, which are essential for male germ cell development.

Date: 2025
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DOI: 10.1038/s41467-025-61733-x

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