Histone demethylase KDM2A recruits HCFC1 and E2F1 to orchestrate male germ cell meiotic entry and progression

In mammals, the transition from mitosis to meiosis facilitates the successful production of gametes. However, the regulatory mechanisms that control meiotic initiation remain unclear, particularly in the context of complex histone modifications. Herein, we show that KDM2A, acting as a lysine demethylase targeting H3K36me3 in male germ cells, plays an essential role in modulating meiotic entry and progression. Conditional deletion of Kdm2a in mouse pre-meiotic germ cells results in complete male sterility, with spermatogenesis ultimately arrested at the zygotene stage of meiosis. KDM2A deficiency disrupts H3K36me2/3 deposition in c-KIT+ germ cells, characterized by a reduction in H3K36me2 but a dramatic increase in H3K36me3. Furthermore, KDM2A recruits the transcription factor E2F1 and its co-factor HCFC1 to the promoters of key genes required for meiosis entry and progression, such as Stra8, Meiosin, Spo11, and Sycp1. Collectively, our study unveils an essential role for KDM2A in mediating H3K36me2/3 deposition and controlling the programmed gene expression necessary for the transition from mitosis to meiosis during spermatogenesis. The role of histone demethylation in spermatogenesis remains incompletely understood. This work shows that KDM2A demethylates trimethylated histone H3 lysine 36 (H3K36me3) and cooperates with the transcription factor E2F1 and its co-factor HCFC1 during the transition from mitosis to meiosis.KDM2A is essential for meiotic initiation and progression by promoting meiotic gene expression and suppressing the expression of genes involved in spermatogonial development.In male germ cells, KDM2A specifically demethylates H3K36me3, thus increasing H3K36me2 levels.KDM2A interacts with E2F1 and HCFC1 to facilitate meiotic gene expression and ensure proper meiotic progression. The balance of H3K36 di- and tri-methylation regulates meiotic gene expression during mouse spermatogenesis.