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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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.
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.
This file contains Supplementary Figures 1-12 with legends and additional references. (PDF 615 kb)
This table shows ChIP-seq identified target genes for Tet1-N, Tet1-C, Sin3A (Abcam), Sin3A (S.Cruz). (XLS 541 kb)
This table shows hmC status of genes reported to become DNA methylated during differentiation. (XLS 82 kb)
This table shows Tet1 knockdown microarray data. (XLS 10245 kb)
This table shows Sin3A knockdown microarray data. (XLS 7690 kb)
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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
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