title: Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells.
abstract: 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.
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Xu
authors.forename: Feizhen
authors.initials: F
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Lingchun
authors.initials: L
authors.lastname: Kong
authors.forename: Lijun
authors.initials: L
authors.lastname: Xiong
authors.forename: Jie
authors.initials: J
authors.lastname: Deng
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Barbera
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zheng
authors.forename: Haikuo
authors.initials: H
authors.lastname: Zhang
authors.forename: Stephen
authors.initials: S
authors.lastname: Huang
authors.forename: Jinrong
authors.initials: J
authors.lastname: Min
authors.forename: Thomas
authors.initials: T
authors.lastname: Nicholson
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Yujiang Geno
authors.initials: YG
authors.lastname: Shi
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases