Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Laboratory Animal Center, Huazhong University of Science and Technology, Wuhan, 430030, China.
EMBO J. 2024 Oct;43(19):4197-4227. doi: 10.1038/s44318-024-00203-4. Epub 2024 Aug 19.
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.
在哺乳动物中，从有丝分裂向减数分裂的转变促进了配子的成功产生。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，我们表明 KDM2A 作为一种赖氨酸去甲基酶，靶向雄性生殖细胞中的 H3K36me3，在调节减数分裂进入和进展中起着至关重要的作用。在小鼠减数分裂前生殖细胞中条件性缺失 Kdm2a 会导致完全雄性不育，精子发生最终停滞在减数分裂的粗线期阶段。KDM2A 缺陷破坏了 c-KIT 生殖细胞中的 H3K36me2/3 沉积，表现为 H3K36me2 的减少，但 H3K36me3 的急剧增加。此外，KDM2A 将转录因子 E2F1 及其辅助因子 HCFC1 募集到减数分裂进入和进展所需的关键基因的启动子上，如 Stra8、Meiosin、Spo11 和 Sycp1。总之，我们的研究揭示了 KDM2A 在介导 H3K36me2/3 沉积以及控制从有丝分裂向减数分裂过渡期间精子发生中所需的程序化基因表达中的重要作用。
