Tet1 and hydroxymethylcytosine in transcription and DNA methylation fidelity

By K. Williams, J. Christensen, M. T. Pedersen, J. Johansen, P. Cloos, Juri Rappsilber, K. Helin. Nature, 2011

1,051 citations recorded by the source corpus.

Enzymes catalysing the methylation of the 5-position of cytosine (mC) have essential roles in regulating gene expression and maintaining cellular identity. Recently, TET1 was found to hydroxylate the methyl group of mC, converting it to 5-hydroxymethyl cytosine (hmC). Here we show that TET1 binds throughout the genome of embryonic stem cells, with the majority of binding sites located at transcription start sites (TSSs) of CpG-rich promoters and within genes. The hmC modification is found in gene bodies and in contrast to mC is also enriched at CpG-rich TSSs. We provide evidence further that TET1 has a role in transcriptional repression. TET1 binds a significant proportion of Polycomb group target genes. Furthermore, TET1 associates and colocalizes with the SIN3A co-repressor complex. We propose that TET1 fine-tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences and thereby contributes to the regulation of DNA methylation fidelity.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/62468f8ed3915d144f432b15c9b38d077cc267f2

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In Molecular Biology

1. Peter A. Jones
2. Hao Wu
3. Yi Zhang
4. S. Baylin
5. Dirk Schübeler
6. Wolf Reik
7. K. Helin
8. Yong Zhang

Citations in the corpus

• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, background): “…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): “…Guo et al., 2011; He et al., 2011; Ito et al., 2011; Koh et al., 2011; Pastor et al., 2011; Popp et al., 2010; Rai et al., 2008; Song et al., 2011; Williams et al., 2011;Wu et al., 2011a, 2011b; Xu et al., 2011) have identified key players in this process, which may have been overlooked…”
• Uncovering the role of 5-hydroxymethylcytosine in the epigenome (2011, background): “A number of recent studies have thus looked at the roles of 5hmC and TET1 in ESCs, adding to the vast amount of existing epigenomic data for this cell typ”
• Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “In addition, in vivo chromatin immunoprecipitation of Tet1 shows that it is highly enriched on CpG islands, most of which are associated with promoters with intermediate and high CpG content, and that this enrichment is lost upon introduction of amutation in the CXXC domain (Williams et al. 2011; Wu”
• DNA-binding factors shape the mouse methylome at distal regulatory regions (2011, background): “One candidate protein responsible for catalysing 5hmC, Tet1 (ref”
• Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011, neutral): “…dynamic interplay between changes in TET1-mediared hy- droxymethylation and other epigenetic marks in regulating gene expression (Ficz et al., 2011; Williams et al., 2011; Wu et al., 2011), and it is likely additional alterations in the epige- netic state cooperate with TET2 mutations in…”
• 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).”
• Epigenetic Determinants of Cancer. (2016, background): “Within these hypomethylated domains, there could also be alterations in function and/or targeting of the recently identified TET proteins, which normally contribute to maintaining promoter CpG islands free of DNA methylation (Williams et al. 2011).”
• Target analysis by integration of transcriptome and ChIP-seq data with BETA (2013, result): “3b ); these finding are consistent with the previous studies 5,39 .”
• 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).”