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TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity

Nature volume 473, pages 343348 (19 May 2011) | Download Citation


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.

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Gene Expression Omnibus

Data deposits

ChIP-seq and gene expression data are available at the Gene Expression Omnibus (GEO) under accession GSE24843.


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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

Author notes

    • Kristine Williams
    • , Jesper Christensen
    •  & Marianne Terndrup Pedersen

    These authors contributed equally to this work.


  1. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark

    • Kristine Williams
    • , Jesper Christensen
    • , Marianne Terndrup Pedersen
    • , Jens V. Johansen
    • , Paul A. C. Cloos
    •  & Kristian Helin
  2. Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark

    • Kristine Williams
    • , Jesper Christensen
    • , Marianne Terndrup Pedersen
    • , Paul A. C. Cloos
    •  & Kristian Helin
  3. The Bioinformatics Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark

    • Jens V. Johansen
  4. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK

    • Juri Rappsilber


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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.

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.

Corresponding author

Correspondence to Kristian Helin.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-12 with legends and additional references.

Excel files

  1. 1.

    Supplementary Table 1

    This table shows ChIP-seq identified target genes for Tet1-N, Tet1-C, Sin3A (Abcam), Sin3A (S.Cruz).

  2. 2.

    Supplementary Table 2

    This table shows hmC status of genes reported to become DNA methylated during differentiation.

  3. 3.

    Supplementary Table 3

    This table shows Tet1 knockdown microarray data.

  4. 4.

    Supplementary Table 4

    This table shows Sin3A knockdown microarray data.

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