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

By Yufei Xu, Feizhen Wu, Li Tan, Lingchun Kong, Li-jun Xiong, Jie Deng, Andrew J. Barbera, Lijuan Zheng, Haikuo Zhang, Stephen A. Huang and 7 more. Molecules and Cells, 2011

651 citations recorded by the source corpus.

SUMMARY 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 unmodified C, 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.

Subfields: Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/408a980574323e45de745cfb7ecea7585f9f9cab

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Hao Wu
2. Yi Zhang
3. Wolf Reik
4. E. Nestler
5. David M. Burns
6. Li Shen
7. Xiaochuan Liu
8. Leonard I. Zon

In Pediatrics, Perinatology and Child Health

1. Yi Zhang
2. Hao Wu
3. Wolf Reik

Citations in the corpus

• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “Wild-type IDH1/2 converts isocitrate to a-KG, whereas mutant IDH enzymes produce 2-hydroxyglutarate (2-HG), an oncometabolite that competitively inhibit many a-KG-dependent dioxygenases, including TET proteins (Figueroa et al., 2010; Xu et al., 2011a).”
• DNA Demethylation Dynamics (2011, background): “However, like methylation, a high concentration of 5hmC correlates with transcriptionally nonproductive or altogether inactive gene promoters (Ficz et al., 2011; Pastor et al., 2011; Williams et al., 2011; Wu et al., 2011a; Xu et al., 2011).”
• LOSS OF 5-HYDROXYMETHYLCYTOSINE IS AN EPIGENETIC HALLMARK OF MELANOMA (2012, positive): “This is not surprising because we and others have shown complex roles of 5-hmC in gene transcription regulation in mouse ES cells (Ficz et al., 2011; Xu et al., 2011b).”
• ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “The distributions of Tet proteins and 5hmC across the genome roughly overlap, while Tet1 and Tet3 prefer CpG enriched regions [50,58].”
• Uncovering the role of 5-hydroxymethylcytosine in the epigenome (2011, background): “By contrast, others have suggested that not only can this domain still bind DNA, but its distinct nature allows it to bind to unmethylated, methylated and hydroxymethylated DNA (unlike the DNMT1 CXXC domain, which binds almost exclusively to unmethylated DNA”
• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “In addition, 2-hydroxyglutarate (2-HG), a competitive inhibitor of 2OG-dependent dioxygenases, suppresses the catalytic activity of Tet proteins (W Xu et al. 2011).”
• Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, neutral): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript al., 2011a; Williams et al., 2011; Wu et al., 2011; Xu et al., 2011).”