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Pramel15 facilitates zygotic nuclear DNMT1 degradation and DNA demethylation

ABSTRACT: Interactome of Pramel15-Flag in TT2 mESCs, two biologocal replicates

ORGANISM(S): Mus Musculus

SUBMITTER: Bing Zhu

PROVIDER: PXD052998 | iProX | Tue Jun 11 00:00:00 BST 2024

REPOSITORIES: iProX

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Pramel15 facilitates zygotic nuclear DNMT1 degradation and DNA demethylation.

Tan Jiajun J Li Yingfeng Y Li Xiang X Zhu Xiaoxiao X Liu Liping L Huang Hua H Wei Jiahua J Wang Hailing H Tian Yong Y Wang Zhigao Z Zhang Zhuqiang Z Zhu Bing B

Nature communications 20240825 1

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, P ...[more]

PMID: 39181896

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Pramel15 facilitates zygotic nuclear DNMT1 degradation and DNA demethylation.

Project description: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.

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