MOE Key Laboratory for Biosystems Homeostasis, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Center for Reproductive Medicine, Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing 100191, China.
Nucleic Acids Res. 2022 Oct 28;50(19):10896-10913. doi: 10.1093/nar/gkac594.
Post-transcriptional RNA modifications critically regulate various biological processes. N4-acetylcytidine (ac4C) is an epi-transcriptome, which is highly conserved in all species. However, the in vivo physiological functions and regulatory mechanisms of ac4C remain poorly understood, particularly in mammals. In this study, we demonstrate that the only known ac4C writer, N-acetyltransferase 10 (NAT10), plays an essential role in male reproduction. We identified the occurrence of ac4C in the mRNAs of mouse tissues and showed that ac4C undergoes dynamic changes during spermatogenesis. Germ cell-specific ablation of Nat10 severely inhibits meiotic entry and leads to defects in homologous chromosome synapsis, meiotic recombination and repair of DNA double-strand breaks during meiosis. Transcriptomic profiling revealed dysregulation of functional genes in meiotic prophase I after Nat10 deletion. These findings highlight the crucial physiological functions of ac4C modifications in male spermatogenesis and expand our understanding of its role in the regulation of specific physiological processes in vivo.
转录后 RNA 修饰对各种生物过程具有关键调控作用。N4-乙酰胞苷（ac4C）是一种 epi-transcriptome，在所有物种中高度保守。然而，ac4C 的体内生理功能和调控机制仍知之甚少，特别是在哺乳动物中。在这项研究中，我们证明了唯一已知的 ac4C 写入器，N-乙酰转移酶 10（NAT10），在男性生殖中发挥着重要作用。我们在小鼠组织的 mRNA 中发现了 ac4C 的存在，并表明 ac4C 在精子发生过程中发生动态变化。生殖细胞特异性 Nat10 缺失严重抑制减数分裂进入，并导致同源染色体联会、减数分裂重组和减数分裂中 DNA 双链断裂修复缺陷。转录组分析显示，Nat10 缺失后减数分裂前期 I 的功能基因失调。这些发现强调了 ac4C 修饰在男性精子发生中的重要生理功能，并扩展了我们对其在体内特定生理过程调控中的作用的理解。
