Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fouse, S. D. et al. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2, 160–169 (2008)
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008)
Mohn, F. et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol. Cell 30, 755–766 (2008)
Saxonov, S., Berg, P. & Brutlag, D. L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl Acad. Sci. USA 103, 1412–1417 (2006)
Takai, D. & Jones, P. A. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc. Natl Acad. Sci. USA 99, 3740–3745 (2002)
Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nature Rev. Genet. 9, 465–476 (2008)
Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nature Rev. Genet. 10, 295–304 (2009)
Gal-Yam, E. N., Saito, Y., Egger, G. & Jones, P. A. Cancer epigenetics: modifications, screening, and therapy. Annu. Rev. Med. 59, 267–280 (2008)
Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009)
Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009)
Szwagierczak, A., Bultmann, S., Schmidt, C. S., Spada, F. & Leonhardt, H. Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res. 38, e181 (2010)
Koh, K. P. et al. Tet1 and tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200–213 (2011)
Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010)
Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11, 805–814 (2006)
Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257 (2010)
Song, C. X. et al. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nature Biotechnol. 29, 68–72 (2011)
Grzenda, A., Lomberk, G., Zhang, J. S. & Urrutia, R. Sin3: master scaffold and transcriptional corepressor. Biochim. Biophys. Acta 1789, 443–450 (2009)
Mohamedali, A. M. et al. Novel TET2 mutations associated with UPD4q24 in myelodysplastic syndrome. J. Clin. Oncol. 27, 4002–4006 (2009)
Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009)
Pasini, D., Bracken, A. P., Hansen, J. B., Capillo, M. & Helin, K. The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol. Cell. Biol. 27, 3769–3779 (2007)
Pasini, D. et al. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306–310 (2010)
Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853–862 (2005)
Ji, H. et al. An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nature Biotechnol. 26, 1293–1300 (2008)
Chavez, L. et al. Computational analysis of genome-wide DNA methylation during the differentiation of human embryonic stem cells along the endodermal lineage. Genome Res. 20, 1441–1450 (2010)
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)
Rahl, P. B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010)
Marson, A. et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521–533 (2008)
Erlanger, B. F. & Beiser, S. M. Antibodies specific for ribonucleosides and ribonucleotides and their reaction with DNA. Proc. Natl Acad. Sci. USA 52, 68–74 (1964)
Rhead, B. et al. The UCSC Genome Browser database: update 2010. Nucleic Acids Res. 38, D613–D619 (2010)
Acknowledgements
We thank U. Toftegaard for excellent technical help, M. Okano for the donation of TKO ES cells, and members of the Helin lab for discussions. M.T.P. was supported by a fellowship from the Danish Cancer Society. J.R. is a senior research fellow of the Wellcome Trust. The work in the Helin lab was supported by grants from the Excellence Program of the University of Copenhagen, the Danish National Research Foundation, the Danish Cancer Society, the Lundbeck foundation, the Novo Nordisk Foundation, and the Danish Medical Research Council.
Author information
Authors and Affiliations
Contributions
K.W. performed the major part of experiments in Figs 1, 3, 4a, b, h and Supplementary Figs 1a–c, 2, 3, 5, 7a, 9a–d, 10a, 11 and 12c, d. J.C. developed and characterized the new reagents used in this study, and participated in most experiments. M.T.P. performed the major part of experiments in Figs 2, 4c, g and Supplementary Figs 1d, 6b, 7b, c, 8, 10b and 12a, b. J.V.J. performed bioinformatics analyses. P.A.C.C. assisted in characterizing reagents. J.R performed the mass spectrometry analysis. J.C. and K.H. supervised the project and all authors contributed to the writing of the manuscript.
Corresponding author
Ethics declarations
Competing interests
K.H., J.C. and P.A.C.C. are cofounders of EpiTherapeutics and have shares and warrants in the company. All other authors declare that they have no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-12 with legends and additional references. (PDF 615 kb)
Supplementary Table 1
This table shows ChIP-seq identified target genes for Tet1-N, Tet1-C, Sin3A (Abcam), Sin3A (S.Cruz). (XLS 541 kb)
Supplementary Table 2
This table shows hmC status of genes reported to become DNA methylated during differentiation. (XLS 82 kb)
Supplementary Table 3
This table shows Tet1 knockdown microarray data. (XLS 10245 kb)
Supplementary Table 4
This table shows Sin3A knockdown microarray data. (XLS 7690 kb)
Rights and permissions
About this article
Cite this article
Williams, K., Christensen, J., Pedersen, M. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011). https://doi.org/10.1038/nature10066
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/nature10066
This article is cited by
-
Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes
Cell & Bioscience (2023)
-
Macrophage migration inhibitory factor is overproduced through EGR1 in TET2low resting monocytes
Communications Biology (2022)
-
Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature
Clinical Epigenetics (2021)
-
Ten-eleven translocation protein 1 modulates medulloblastoma progression
Genome Biology (2021)
-
Ten-eleven translocation 1 mediated-DNA hydroxymethylation is required for myelination and remyelination in the mouse brain
Nature Communications (2021)
Yuesheng Xia
Focus on TET1: natural or factitious regulation of DNA methylation in embryogenesis and cancer
We respect Kristine Williams et al for their research, which determine the understanding essence of DNA methylation in embryogenesis and cancer. DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation, the methylated or unmethylated status of a CpG site is function as a cellular memory. Genome-wide quantitative assessment proclaims genome-wide variation of DNA methylation patterns, compared to normal tissue controls, some
tumors exhibit greater methylation entropies (Nucl Acids Res 39,1?10;2011), many cancer cells have decreased fidelity in replicating methylation patterns in some CpG islands, and that the decrease could lead to methylation of the entire CpG islands (Cancer Res 65, 11-117;2005). Natural regulation or factitious embellish of DNA methylation display active promoter (Nature 452,45-50;2008), however it lacks specific goal, Kristine Williams et al's study provide a new target for cancer treatment.
Jianhua Wang, Mei Shi, Yuesheng Xia
Xijing Hospital, Fourth Military Medical University, China
E-mail: [email protected] [email protected]
Jianhua Wang
TET1 implicates vital regulation on life: DNA methylation
We respect Kristine Williams et al for their research, which determine the natural process of DNA methylation in embryogenesis. DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation, the methylated or unmethylated status of a CpG site is function as a cellular memory. Genome-wide quantitative assessment proclaims genome-wide variation of DNA methylation patterns, compared to normal tissue controls, some tumors exhibit greater methylation entropies to decrease fidelity in replicating methylation patterns in some CpG islands. Factitious regulation of DNA methylation display active promoter and is beneficial to cancer to change process. However, TET1 provide a new target for cancer treatment.
Jianhua Wang, Mei Shi
Xijing Hospital, Fourth Military Medical University, China
E-mail: [email protected]