Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells

By Hao Wu, A. D’Alessio, Shinsuke Ito, K. Xia, Zhibin Wang, Kairong Cui, Keji Zhao, Y. Sun, Yi Zhang. Nature, 2011

688 citations recorded by the source corpus.

Epigenetic modification of the mammalian genome by DNA methylation (5-methylcytosine) has a profound impact on chromatin structure, gene expression and maintenance of cellular identity. The recent demonstration that members of the Ten-eleven translocation (Tet) family of proteins can convert 5-methylcytosine to 5-hydroxymethylcytosine raised the possibility that Tet proteins are capable of establishing a distinct epigenetic state. We have recently demonstrated that Tet1 is specifically expressed in murine embryonic stem (ES) cells and is required for ES cell maintenance. Using chromatin immunoprecipitation coupled with high-throughput DNA sequencing, here we show in mouse ES cells that Tet1 is preferentially bound to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Despite an increase in levels of DNA methylation at many Tet1-binding sites, Tet1 depletion does not lead to downregulation of all the Tet1 targets. Interestingly, although Tet1-mediated promoter hypomethylation is required for maintaining the expression of a group of transcriptionally active genes, it is also involved in repression of Polycomb-targeted developmental regulators. Tet1 contributes to silencing of this group of genes by facilitating recruitment of PRC2 to CpG-rich gene promoters. Thus, our study not only establishes a role for Tet1 in modulating DNA methylation levels at CpG-rich promoters, but also reveals a dual function of Tet1 in promoting transcription of pluripotency factors as well as participating in the repression of Polycomb-targeted developmental regulators.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9ee088c2c441080eb8739566889a6de3dda5f851

How researchers see this paper

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

In Genetics

1. Yi Zhang
2. Hao Wu
3. Peter A. Jones
4. S. Baylin
5. A. Bird
6. Wolf Reik
7. Peng Jin
8. Keith E. Szulwach

In Molecular Biology

1. Hao Wu
2. Yi Zhang
3. Peter A. Jones
4. S. Baylin
5. A. Bird
6. J. Simon
7. Chuan He
8. Wolf Reik

Citations in the corpus

• Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, methodology): “…repressed lineage-specific genes (Wu et al. 2011b), whereas a cohort of actively transcribed Tet1 target genes, including several pluripotency-related transcription factors (e.g., Nanog, Tcl1, and Esrrb), are found to be downregulated in the absence of Tet1 (Ficz et al. 2011; Wu et al. 2011b).”
• A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “The localization of the TET enzymes, and increased levels of 5-hydroxymethylcytosine, at CpG island promoters of the genes that are most vulnerable to cancer-specific DNA hypermethylation (those with bivalent chromati”
• 5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging (2011, background): “Previous observations have suggested that TSS-associated 5-mC hydroxylation, via Tet family proteins, is involved in both maintaining gene expression of pluripotent associated genes and poising expression of developmentally regulated genes in ES cell”
• CpG islands and the regulation of transcription. (2011, positive): “Compatible with this hypothesis, recent studies locate Tet1 preferentially at CGIs in mouse ES cells (Ficz et al. 2011; Wu et al. 2011a,b), and depletion of Tet1 results in increased CpG methylation at CGIs (Wu et al. 2011a).”
• WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, neutral): “Such diverse and complex roles are consistent with the binding of TET proteins and the distribution of their catalytic products, 5hmC, 5fC and 5caC throughout the genome (Shen et al., 2013; Song et al., 2013; Williams et al., 2011; Wu et al., 2011).”
• The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells (2012, neutral): “2011; Williams et al., 2011; Wu et al., 2011).”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “…Regulation Genomic mapping of TET proteins in ESCs, HEK293T cells and bone marrow tissues suggest that all three TET proteins are preferentially localized to unmethylated CpG-rich promoters (Chen et al., 2013b; Deplus et al., 2013; Vella et al., 2013; Williams et al., 2011; Wu et al., 2011b).”
• DNA Demethylation Dynamics (2011, background): “An unexpected complication of interpretations of experiments regarding the effects of TET proteins on gene expression is that TET1 plays a repressive role, independent of its enzymatic activity as a hydroxylase (Williams et al., 2011; Wu et al., 2011b).”
• Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes (2013, neutral): “The products of the Tet genes are associated with most active promoters and are responsible for global 5-hydroxymethylation of DNA in ESCs (Wu et al., 2011; Yu et al., 2012a).”
• Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put (2013, background): “Methylation of CpG blocks KDM2B binding, a finding that resonates with the impact of the Tet1 protein on PRC2 recruitment (Wu et al., 2011); perhaps other proteins involved in targeting both PRC1 and PRC2 are impacted by CpG methylation, or perhaps there is feedback between KDM2B-mediated PRC1…”
• ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “5hmC plays an important role in stem cell differentiation, where its conversion from 5mC is mediated by Tet1 [49,51,55,59].”