Genome-wide Regulation of 5hmC, 5mC, and Gene Expression by Tet1 Hydroxylase in Mouse Embryonic Stem Cells

• Published in: Molecular cell Vol. 42; no. 4; pp. 451 - 464
• Main Authors: Xu, Yufei, Wu, Feizhen, Tan, Li, Kong, Lingchun, Xiong, Lijun, Deng, Jie, Barbera, Andrew J., Zheng, Lijuan, Zhang, Haikuo, Huang, Stephen, Min, Jinrong, Nicholson, Thomas, Chen, Taiping, Xu, Guoliang, Shi, Yang, Zhang, Kun, Shi, Yujiang Geno
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-05-2011
• Subjects: 5-Methylcytosine - metabolism; Animals; Antagonism; CpG islands; Cytosine; Cytosine - analogs & derivatives; Cytosine - metabolism; Data processing; Differentiation; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA methylation; DNA methyltransferase; DNA-Binding Proteins - metabolism; Embryo cells; Embryogenesis; embryonic stem cells; Embryonic Stem Cells - enzymology; epigenetics; Gene expression; Gene Expression Regulation, Developmental; Gene mapping; genes; Genome-Wide Association Study; Genomes; Hydroxylase; methyltransferases; Mice; Mixed Function Oxygenases - metabolism; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins - metabolism; Stem cells; Translocation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.04.005

DNA methylation at the 5 position of cytosine (5mC) in the mammalian genome is a key epigenetic event critical for various cellular processes. The ten-eleven translocation (Tet) family of 5mC-hydroxylases, which convert 5mC to 5-hydroxymethylcytosine (5hmC), offers a way for dynamic regulation of DNA methylation. Here we report that Tet1 binds to unmodified C or 5mC- or 5hmC-modified CpG-rich DNA through its CXXC domain. Genome-wide mapping of Tet1 and 5hmC reveals mechanisms by which Tet1 controls 5hmC and 5mC levels in mouse embryonic stem cells (mESCs). We also uncover a comprehensive gene network influenced by Tet1. Collectively, our data suggest that Tet1 controls DNA methylation both by binding to CpG-rich regions to prevent unwanted DNA methyltransferase activity, and by converting 5mC to 5hmC through hydroxylase activity. This Tet1-mediated antagonism of CpG methylation imparts differential maintenance of DNA methylation status at Tet1 targets, ultimately contributing to mESC differentiation and the onset of embryonic development.
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► Defined Tet1 as a CpG-rich DNA-binding protein that binds to C, 5mC, and 5hmC ► Established genome-wide maps of 5hmC, Tet1, and Tet1-associated gene profiling ► Revealed complex modes of Tet1 action in 5mC, 5hmC, and gene expression regulations ► Provided a basis for understanding how Tet1 and 5hmC contribute to ESC epigenome