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.

中文翻译：

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组蛋白去甲基化酶 KDM2A 招募 HCFC1 和 E2F1 来协调雄性生殖细胞减数分裂的进入和进展。


在哺乳动物中，从有丝分裂到减数分裂的转变有助于配子的成功产生。然而，控制减数分裂起始的调节机制仍不清楚，特别是在复杂的组蛋白修饰的背景下。在此，我们证明 KDM2A 作为雄性生殖细胞中 H3K36me3 的赖氨酸脱甲基酶，在调节减数分裂进入和进展中发挥着重要作用。小鼠减数分裂前生殖细胞中 Kdm2a 的条件性缺失会导致完全雄性不育，精子发生最终在减数分裂的合子期停止。 KDM2A 缺陷会破坏 c-KIT+ 生殖细胞中的 H3K36me2/3 沉积，其特征是 H3K36me2 减少，但 H3K36me3 急剧增加。此外，KDM2A 将转录因子 E2F1 及其辅助因子 HCFC1 招募到减数分裂进入和进展所需的关键基因的启动子，例如 Stra8、Meiosin、Spo11 和 Sycp1。总的来说，我们的研究揭示了 KDM2A 在介导 H3K36me2/3 沉积和控制精子发生过程中从有丝分裂到减数分裂过渡所需的程序化基因表达方面的重要作用。