National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Epigenetic Regulation and Intervention, Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2024 Aug 25;15(1):7310. doi: 10.1038/s41467-024-51614-0.
In mammals, global passive demethylation contributes to epigenetic reprogramming during early embryonic development. At this stage, the majority of DNA-methyltransferase 1 (DNMT1) protein is excluded from nucleus, which is considered the primary cause. However, whether the remaining nuclear activity of DNMT1 is regulated by additional mechanisms is unclear. Here, we report that nuclear DNMT1 abundance is finetuned through proteasomal degradation in mouse zygotes. We identify a maternal factor, Pramel15, which targets DNMT1 for degradation via Cullin-RING E3 ligases. Loss of Pramel15 elevates DNMT1 levels in the zygote pronuclei, impairs zygotic DNA demethylation, and causes a stochastic gain of DNA methylation in early embryos. Thus, Pramel15 can modulate the residual level of DNMT1 in the nucleus during zygotic DNA replication, thereby ensuring efficient DNA methylation reprogramming in early embryos.
在哺乳动物中，整体的被动去甲基化有助于胚胎早期发育过程中的表观遗传重编程。在这个阶段，大多数 DNA 甲基转移酶 1（DNMT1）蛋白被排除在核外，这被认为是主要原因。然而，DNMT1 的剩余核活性是否受到其他机制的调节尚不清楚。在这里，我们报告说，在小鼠受精卵中，DNMT1 的核丰度通过蛋白酶体降解进行微调。我们鉴定出一种母源因子 Pramel15，它通过 Cullin-RING E3 连接酶将 DNMT1 靶向降解。Pramel15 的缺失会增加受精卵原核中的 DNMT1 水平，破坏受精卵的 DNA 去甲基化，并导致早期胚胎中 DNA 甲基化的随机获得。因此，Pramel15 可以在受精卵 DNA 复制过程中调节核内残留的 DNMT1 水平，从而确保早期胚胎中有效的 DNA 甲基化重编程。
