Skip to main content

Thank you for visiting 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.

PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos


The modification of DNA by 5-methylcytosine (5mC) has essential roles in cell differentiation and development through epigenetic gene regulation1. 5mC can be converted to another modified base, 5-hydroxymethylcytosine (5hmC), by the tet methylcytosine dioxygenase (Tet) family of enzymes2,3. Notably, the balance between 5hmC and 5mC in the genome is linked with cell-differentiation processes such as pluripotency and lineage commitment4,5,6,7. We have previously reported that the maternal factor PGC7 (also known as Dppa3, Stella) is required for the maintenance of DNA methylation in early embryogenesis, and protects 5mC from conversion to 5hmC in the maternal genome8,9. Here we show that PGC7 protects 5mC from Tet3-mediated conversion to 5hmC by binding to maternal chromatin containing dimethylated histone H3 lysine 9 (H3K9me2) in mice. In addition, imprinted loci that are marked with H3K9me2 in mature sperm are protected by PGC7 binding in early embryogenesis. This type of regulatory mechanism could be involved in DNA modifications in somatic cells as well as in early embryos.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Preferential binding of PGC7 to H3K9me2-marked chromatin.
Figure 2: Protection of the maternal genome from DNA demethylation by PGC7 through H3K9me2-containing chromatin in early embryos.
Figure 3: Remaining H3K9me2 at the DMRs of two paternally imprinted genes, H19 and Rasgrf1 , in mature sperm.
Figure 4: Protection of the conversion of 5mC to 5hmC by PGC7 through H3K9me2-containing chromatin in early embryos.


  1. 1

    Feng, S., Jacobsen, S. E. & Reik, W. Epigenetic reprogramming in plant and animal development. Science 330, 622–627 (2010)

    ADS  CAS  Article  Google Scholar 

  2. 2

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

    ADS  CAS  Article  Google Scholar 

  3. 3

    Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Koh, K. 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)

    CAS  Article  Google Scholar 

  5. 5

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

    ADS  CAS  Article  Google Scholar 

  6. 6

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

    ADS  CAS  Article  Google Scholar 

  7. 7

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

    ADS  CAS  Article  Google Scholar 

  8. 8

    Nakamura, T. et al. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nature Cell Biol. 9, 64–71 (2007)

    CAS  Article  Google Scholar 

  9. 9

    Wossidlo, M. et al. 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nature Commun. 2, 241 (2011)

    Article  Google Scholar 

  10. 10

    Santos, F., Peters, A. H., Otte, A. P., Reik, W. & Dean, W. Dynamic chromatin modifications characterise the first cell cycle in mouse embryos. Dev. Biol. 280, 225–236 (2005)

    CAS  Article  Google Scholar 

  11. 11

    Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002)

    CAS  Article  Google Scholar 

  12. 12

    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)

    CAS  Article  Google Scholar 

  13. 13

    Ge, Y. Z. et al. Chromatin targeting of de novo DNA methyltransferases by the PWWP domain. J. Biol. Chem. 279, 25447–25454 (2004)

    CAS  Article  Google Scholar 

  14. 14

    Hajkova, P. et al. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science 329, 78–82 (2010)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006)

    CAS  Article  Google Scholar 

  16. 16

    Olek, A. & Walter, J. The pre-implantation ontogeny of the H19 methylation imprint. Nature Genet. 17, 275–276 (1997)

    CAS  Article  Google Scholar 

  17. 17

    Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nature Struct. Mol. Biol. 17, 679–687 (2010)

    CAS  Article  Google Scholar 

  19. 19

    Farthing, C. R. et al. Global mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genes. PLoS Genet. 4, e1000116 (2008)

    Article  Google Scholar 

  20. 20

    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)

    ADS  CAS  Article  Google Scholar 

  21. 21

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

    ADS  CAS  Article  Google Scholar 

  22. 22

    Liu, Z. et al. Jmjd1a demethylase-regulated histone modification is essential for cAMP-response element modulator-refulated gene expression and spermatogenesis. J. Biol. Chem. 285, 2758–2770 (2010)

    CAS  Article  Google Scholar 

  23. 23

    Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011)

    ADS  CAS  Article  Google Scholar 

  24. 24

    He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Pogribny, I., Yi, P. & James, S. A sensitive new method for rapid detection of abnormal methylation patterns in global DNA and within CpG islands. Biochem. Biophys. Res. Commun. 262, 624–628 (1999)

    CAS  Article  Google Scholar 

Download references


We thank M. Okano, H. Niwa and H. Kimura for providing Dnmt1−/−Dnmt3a−/−Dnmt3b−/−ES cells, plasmids and antibody. We also thank N. Asada for assistance, and A. Mizokami and M. Imaizumi for secretarial assistance. This work was supported in part by grants from the Ministry of Education, Science, Sports, Culture and Technology of Japan.

Author information




T. Nakamura and T. Nakano conceived the project and wrote the manuscript. T. Nakamura designed and performed the all experiments and evaluated the results. Y.-J.L., H.N. and H.U. propagated PGC7−/− mice. K.I., S.M. and A.O. performed some of the experiments. M.T. and Y.S. provided G9a−/− ES cells and related materials.

Corresponding authors

Correspondence to Toshinobu Nakamura or Toru Nakano.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary References, Supplementary Figures 1-22 and Supplementary Tables 1-2. (PDF 7551 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nakamura, T., Liu, YJ., Nakashima, H. et al. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486, 415–419 (2012).

Download citation

Further reading


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.


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