Pramel15 facilitates zygotic nuclear DNMT1 degradation and DNA demethylation
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.
Authors
- Jiajun Tan (ORCID: https://orcid.org/0009-0007-2658-0030)
- Zhigao Wang (ORCID: https://orcid.org/0000-0002-6544-4302)
- Zhuqiang Zhang (ORCID: https://orcid.org/0000-0001-6513-2854)
- Yong Tian (ORCID: https://orcid.org/0000-0002-8790-1148)
- Bing Zhu (ORCID: https://orcid.org/0000-0003-2049-432X)
- Xiaoxiao Zhu (ORCID: https://orcid.org/0000-0002-7086-4256)
- Jiahua Wei (ORCID: https://orcid.org/0000-0002-8607-2368)
- Liping Liu (ORCID: https://orcid.org/0009-0008-4890-9981)
- Hua Huang (ORCID: https://orcid.org/0000-0002-8936-3371)
- Yi Li (ORCID: https://orcid.org/0000-0001-9292-8604)
- Xiang Li (ORCID: https://orcid.org/0000-0003-0724-0982)
- Yingfeng Li (ORCID: https://orcid.org/0000-0002-9492-9931)
Institutions
- Chinese Academy of Sciences (CN)
- University of South Florida (US)
- Institute of Acoustics (CN)
- Institute of Biophysics (CN)
- Research Center for Eco-Environmental Sciences (CN)
- University of Chinese Academy of Sciences (CN)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-25
- DOI
- https://doi.org/10.1038/s41467-024-51614-0
- Citations
- 6
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Chinese Academy of Sciences
- Ministry of Science and Technology of the People's Republic of China
- Youth Innovation Promotion Association
- Institute of Biophysics, Chinese Academy of Sciences