Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

TET2 promotes histone O-GlcNAcylation during gene transcription

Nature volume 493, pages 561–564 (2013)Cite this article

Subjects

This article has been updated

Abstract

Ten eleven translocation (TET) enzymes, including TET1, TET2 and TET3, convert 5-methylcytosine to 5-hydroxymethylcytosine1 and regulate gene transcription2,3,4,5. However, the molecular mechanism by which TET family enzymes regulate gene transcription remains elusive5,6. Using protein affinity purification, here we search for functional partners of TET proteins, and find that TET2 and TET3 associate with O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT), an enzyme that by itself catalyses the addition of O-GlcNAc onto serine and threonine residues (O-GlcNAcylation) in vivo7,8. TET2 directly interacts with OGT, which is important for the chromatin association of OGT in vivo. Although this specific interaction does not regulate the enzymatic activity of TET2, it facilitates OGT-dependent histone O-GlcNAcylation. Moreover, OGT associates with TET2 at transcription start sites. Downregulation of TET2 reduces the amount of histone 2B Ser 112 GlcNAc marks in vivo, which are associated with gene transcription regulation. Taken together, these results reveal a TET2-dependent O-GlcNAcylation of chromatin. The double epigenetic modifications on both DNA and histones by TET2 and OGT coordinate together for the regulation of gene transcription.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TET2 forms a complex with OGT.
Figure 2: TET2 enhances histone glycosylation.
Figure 3: TET2 regulates H2B Ser 112 GlcNAc and gene transcription.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The ChIP-seq and microarray data have been deposited in the Gene Expression Omnibus under accession number GSE41720.

Change history

  • 23 January 2013

    An additional affiliation was added for author R.J.

References

  1. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009)

    Article  ADS  CAS  Google Scholar 

  2. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011)

    Article  ADS  CAS  Google Scholar 

  3. Pastor, W. A. et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473, 394–397 (2011)

    Article  ADS  CAS  Google Scholar 

  4. Xu, Y. et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451–464 (2011)

    Article  CAS  Google Scholar 

  5. Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011)

    Article  ADS  CAS  Google Scholar 

  6. 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)

    Article  ADS  CAS  Google Scholar 

  7. Vosseller, K., Sakabe, K., Wells, L. & Hart, G. W. Diverse regulation of protein function by O-GlcNAc: a nuclear and cytoplasmic carbohydrate post-translational modification. Curr. Opin. Chem. Biol. 6, 851–857 (2002)

    Article  CAS  Google Scholar 

  8. Kreppel, L. K., Blomberg, M. A. & Hart, G. W. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J. Biol. Chem. 272, 9308–9315 (1997)

    Article  CAS  Google Scholar 

  9. Gu, T. P. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606–610 (2011)

    Article  ADS  CAS  Google Scholar 

  10. Clarke, A. J. et al. Structural insights into mechanism and specificity of O-GlcNAc transferase. EMBO J. 27, 2780–2788 (2008)

    Article  CAS  Google Scholar 

  11. Martinez-Fleites, C. et al. Structure of an O-GlcNAc transferase homolog provides insight into intracellular glycosylation. Nature Struct. Mol. Biol. 15, 764–765 (2008)

    Article  CAS  Google Scholar 

  12. Lazarus, M. B., Nam, Y., Jiang, J., Sliz, P. & Walker, S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469, 564–567 (2011)

    Article  ADS  CAS  Google Scholar 

  13. Borst, P. & Sabatini, R. Base J: discovery, biosynthesis, and possible functions. Annu. Rev. Microbiol. 62, 235–251 (2008)

    Article  CAS  Google Scholar 

  14. Zhang, S., Roche, K., Nasheuer, H. P. & Lowndes, N. F. Modification of histones by sugar β-N-acetylglucosamine (GlcNAc) occurs on multiple residues, including histone H3 serine 10, and is cell cycle-regulated. J. Biol. Chem. 286, 37483–37495 (2011)

    Article  CAS  Google Scholar 

  15. Fujiki, R. et al. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature 480, 557–560 (2011)

    Article  ADS  CAS  Google Scholar 

  16. Sakabe, K., Wang, Z. & Hart, G. W. β-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc. Natl Acad. Sci. USA 107, 19915–19920 (2010)

    Article  ADS  CAS  Google Scholar 

  17. Fong, J. J. et al. β-N-Acetylglucosamine (O-GlcNAc) is a novel regulator of mitosis-specific phosphorylations on histone H3. J. Biol. Chem. 287, 12195–12203 (2012)

    Article  CAS  Google Scholar 

  18. Capotosti, F. et al. O-GlcNAc transferase catalyzes site-specific proteolysis of HCF-1. Cell 144, 376–388 (2011)

    Article  CAS  Google Scholar 

  19. Yang, X., Zhang, F. & Kudlow, J. E. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell 110, 69–80 (2002)

    Article  CAS  Google Scholar 

  20. Kreppel, L. K. & Hart, G. W. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J. Biol. Chem. 274, 32015–32022 (1999)

    Article  CAS  Google Scholar 

  21. Iyer, S. P., Akimoto, Y. & Hart, G. W. Identification and cloning of a novel family of coiled-coil domain proteins that interact with O-GlcNAc transferase. J. Biol. Chem. 278, 5399–5409 (2003)

    Article  CAS  Google Scholar 

  22. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    Article  ADS  CAS  Google Scholar 

  23. Branco, M. R., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nature Rev. Genet. 13, 7–13 (2012)

    Article  CAS  Google Scholar 

  24. Iqbal, K., Jin, S. G., Pfeifer, G. P. & Szabo, P. E. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc. Natl Acad. Sci. USA 108, 3642–3647 (2011)

    Article  ADS  CAS  Google Scholar 

  25. Inoue, A. & Zhang, Y. Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science 334, 194 (2011)

    Article  ADS  CAS  Google Scholar 

  26. Wu, H. et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 25, 679–684 (2011)

    Article  CAS  Google Scholar 

  27. Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011)

    Article  ADS  CAS  Google Scholar 

  28. Sakabe, K. & Hart, G. W. O-GlcNAc transferase regulates mitotic chromatin dynamics. J. Biol. Chem. 285, 34460–34468 (2010)

    Article  CAS  Google Scholar 

  29. Gambetta, M. C., Oktaba, K. & Muller, J. Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science 325, 93–96 (2009)

    Article  ADS  CAS  Google Scholar 

  30. Sinclair, D. A. et al. Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc. Natl Acad. Sci. USA 106, 13427–13432 (2009)

    Article  ADS  CAS  Google Scholar 

  31. Shechter, D., Dormann, H. L., Allis, C. D. & Hake, S. B. Extraction, purification and analysis of histones. Nature Protocols 2, 1445–1457 (2007)

    Article  CAS  Google Scholar 

  32. Fujiki, R. et al. GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459, 455–459 (2009)

    Article  ADS  CAS  Google Scholar 

  33. Robinson, K. A., Ball, L. E. & Buse, M. G. Reduction of O-GlcNAc protein modification does not prevent insulin resistance in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. 292, E884–E890 (2007)

    Article  CAS  Google Scholar 

  34. Ko, M. et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010)

    Article  ADS  CAS  Google Scholar 

  35. Yang, Z. et al. MicroRNA hsa-miR-138 inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells through adenovirus EID-1. Stem Cells Dev. 20, 259–267 (2011)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Kuang for proofreading the manuscript and J. Hutchins for research support. This work was supported by the National Institutes of Health (CA132755 and CA130899 to X.Y.), the University of Michigan Cancer Center and GI Peptide Research Center. X.Y. is a recipient of the Era of Hope Scholar Award from the Department of Defense.

Author information

Authors and Affiliations

  1. Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 1150 West Medical Center Drive, 5560A MSRBII, Ann Arbor, Michigan 48109, USA,

    Qiang Chen, Yibin Chen, Chunjing Bian & Xiaochun Yu

  2. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan,

    Ryoji Fujiki

  3. JST, PRESTO, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan,

    Ryoji Fujiki

Authors
  1. Qiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yibin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunjing Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryoji Fujiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaochun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.Y. conceived the project and designed the experiments; Q.C. performed the experiments with Y.C., C.B. and R.F.; Q.C. and X.Y. analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Xiaochun Yu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-20 additional references and Supplementary Table 7 (see separate file zipped for Supplementary Tables 1-6). (PDF 2759 kb)

Supplementary Tables

This file contains Supplementary Tables 1-6. (ZIP 2430 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Q., Chen, Y., Bian, C. et al. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564 (2013). https://doi.org/10.1038/nature11742

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11742

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing