Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells

Mol Cell. 2011 May 20;42(4):451-64. doi: 10.1016/j.molcel.2011.04.005. Epub 2011 Apr 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism*
  • Animals
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • Embryonic Stem Cells / enzymology*
  • Gene Expression Regulation, Developmental*
  • Genome-Wide Association Study
  • Mice
  • Mixed Function Oxygenases / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • Mixed Function Oxygenases
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases

Associated data

  • GEO/GSE28500