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Cell Stem Cell. 2014 Oct 2;15(4):447-459. doi: 10.1016/j.stem.2014.08.003. Epub 2014 Sep 15.

Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote.

Author information

1
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
2
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
3
Group of Epigenetic Reprogramming, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
4
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
5
Centre for Molecular Biosciences, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK.
6
Group of Epigenetic Reprogramming, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: jsli@sibcb.ac.cn.
7
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China; Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Peking University, Beijing 100871, China. Electronic address: tangfuchou@pku.edu.cn.
8
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: glxu@sibcb.ac.cn.

Abstract

The epigenomes of mammalian sperm and oocytes, characterized by gamete-specific 5-methylcytosine (5mC) patterns, are reprogrammed during early embryogenesis to establish full developmental potential. Previous studies have suggested that the paternal genome is actively demethylated in the zygote while the maternal genome undergoes subsequent passive demethylation via DNA replication during cleavage. Active demethylation is known to depend on 5mC oxidation by Tet dioxygenases and excision of oxidized bases by thymine DNA glycosylase (TDG). Here we show that both maternal and paternal genomes undergo widespread active and passive demethylation in zygotes before the first mitotic division. Passive demethylation was blocked by the replication inhibitor aphidicolin, and active demethylation was abrogated by deletion of Tet3 in both pronuclei. At actively demethylated loci, 5mCs were processed to unmodified cytosines. Surprisingly, the demethylation process was unaffected by the deletion of TDG from the zygote, suggesting the existence of other demethylation mechanisms downstream of Tet3-mediated oxidation.

PMID:
25220291
DOI:
10.1016/j.stem.2014.08.003
[Indexed for MEDLINE]
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