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:

Chromatin dynamics during epigenetic reprogramming in the mouse germ line

Abstract

A unique feature of the germ cell lineage is the generation of totipotency. A critical event in this context is DNA demethylation and the erasure of parental imprints in mouse primordial germ cells (PGCs) on embryonic day 11.5 (E11.5) after they enter into the developing gonads1,2. Little is yet known about the mechanism involved, except that it is apparently an active process. We have examined the associated changes in the chromatin to gain further insights into this reprogramming event. Here we show that the chromatin changes occur in two steps. The first changes in nascent PGCs at E8.5 establish a distinctive chromatin signature that is reminiscent of pluripotency. Next, when PGCs are residing in the gonads, major changes occur in nuclear architecture accompanied by an extensive erasure of several histone modifications and exchange of histone variants. Furthermore, the histone chaperones HIRA and NAP-1 (NAP111), which are implicated in histone exchange, accumulate in PGC nuclei undergoing reprogramming. We therefore suggest that the mechanism of histone replacement is critical for these chromatin rearrangements to occur. The marked chromatin changes are intimately linked with genome-wide DNA demethylation. On the basis of the timing of the observed events, we propose that if DNA demethylation entails a DNA repair-based mechanism, the evident histone replacement would represent a repair-induced response event rather than being a prerequisite.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: After the entry of PGCs into the gonads, germ cell chromatin undergoes rapid conformational changes.
Figure 2: Chromatin changes observed in PGCs at E11.5.
Figure 3: Separation and analysis of PGCs undergoing distinct phases of the reprogramming process.
Figure 4: Possible connections between chromatin changes and the DNA demethylation process.

Similar content being viewed by others

References

  1. Hajkova, P. et al. Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117, 15–23 (2002)

    Article  CAS  PubMed  Google Scholar 

  2. Lee, J. et al. Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129, 5697–5706 (2002)

    Article  CAS  PubMed  Google Scholar 

  3. Saitou, M. et al. Specification of germ cell fate in mice. Phil. Trans. R. Soc. Lond. B 358, 1363–1370 (2003)

    Article  CAS  Google Scholar 

  4. Ohinata, Y. et al. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436, 207–213 (2005)

    Article  CAS  ADS  PubMed  Google Scholar 

  5. Ancelin, K. et al. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nature Cell Biol. 8, 623–630 (2006)

    Article  CAS  PubMed  Google Scholar 

  6. Seki, Y. et al. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development 134, 2627–2638 (2007)

    Article  CAS  PubMed  Google Scholar 

  7. Surani, M. A. et al. Mechanism of mouse germ cell specification: a genetic program regulating epigenetic reprogramming. Cold Spring Harb. Symp. Quant. Biol. 69, 1–9 (2004)

    Article  CAS  PubMed  Google Scholar 

  8. Allegrucci, C., Thurston, A., Lucas, E. & Young, L. Epigenetics and the germline. Reproduction 129, 137–149 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Cuthbert, G. L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545–553 (2004)

    Article  CAS  PubMed  Google Scholar 

  11. Wang, Y. et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004)

    Article  CAS  ADS  PubMed  Google Scholar 

  12. Henikoff, S., Furuyama, T. & Ahmad, K. Histone variants, nucleosome assembly and epigenetic inheritance. Trends Genet. 20, 320–326 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. Kaufman, P. D. & Almouzni, G. in DNA Replication and Human Disease (ed. DePamphilis, M. L.) 121–40 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2006)

    Google Scholar 

  14. Zweidler, A. Resolution of histones by polyacrylamide gel electrophoresis in presence of nonionic detergents. Methods Cell Biol. 17, 223–233 (1978)

    Article  CAS  PubMed  Google Scholar 

  15. Tagami, H., Ray-Gallet, D., Almouzni, G. & Nakatani, Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116, 51–61 (2004)

    Article  CAS  PubMed  Google Scholar 

  16. Kepert, J. F., Mazurkiewicz, J., Heuvelman, G. L., Toth, K. F. & Rippe, K. NAP1 modulates binding of linker histone H1 to chromatin and induces an extended chromatin fiber conformation. J. Biol. Chem. 280, 34063–34072 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Levchenko, V. & Jackson, V. Histone release during transcription: NAP1 forms a complex with H2A and H2B and facilitates a topologically dependent release of H3 and H4 from the nucleosome. Biochemistry 43, 2359–2372 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Park, Y. J., Chodaparambil, J. V., Bao, Y., McBryant, S. J. & Luger, K. Nucleosome assembly protein 1 exchanges histone H2A–H2B dimers and assists nucleosome sliding. J. Biol. Chem. 280, 1817–1825 (2005)

    Article  CAS  PubMed  Google Scholar 

  19. Lorch, Y., Maier-Davis, B. & Kornberg, R. D. Chromatin remodeling by nucleosome disassembly in vitro. Proc. Natl Acad. Sci. USA 103, 3090–3093 (2006)

    Article  CAS  ADS  PubMed  Google Scholar 

  20. Walfridsson, J., Khorosjutina, O., Matikainen, P., Gustafsson, C. M. & Ekwall, K. A genome-wide role for CHD remodelling factors and Nap1 in nucleosome disassembly. EMBO J. 26, 2868–2879 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Durcova-Hills, G. et al. Influence of sex chromosome constitution on the genomic imprinting of germ cells. Proc. Natl Acad. Sci. USA 103, 11184–11188 (2006)

    Article  CAS  ADS  PubMed  Google Scholar 

  22. Paulsen, M. et al. Sequence conservation and variability of imprinting in the Beckwith–Wiedemann syndrome gene cluster in human and mouse. Hum. Mol. Genet. 9, 1829–1841 (2000)

    Article  CAS  PubMed  Google Scholar 

  23. Choi, Y. et al. DEMETER, a DNA glycosylase domain protein, is required for endosperm gene imprinting and seed viability in Arabidopsis. Cell 110, 33–42 (2002)

    Article  CAS  PubMed  Google Scholar 

  24. Gehring, M. et al. DEMETER DNA glycosylase establishes MEDEA polycomb gene self-imprinting by allele-specific demethylation. Cell 124, 495–506 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gong, Z. et al. ROS1, a repressor of transcriptional gene silencing in Arabidopsis, encodes a DNA glycosylase/lyase. Cell 111, 803–814 (2002)

    Article  CAS  PubMed  Google Scholar 

  26. Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14, R47–R58 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. Green, C. M. & Almouzni, G. When repair meets chromatin. First in series on chromatin dynamics. EMBO Rep. 3, 28–33 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nilsen, H., Lindahl, T. & Verreault, A. DNA base excision repair of uracil residues in reconstituted nucleosome core particles. EMBO J. 21, 5943–5952 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Polo, S. E., Roche, D. & Almouzni, G. New histone incorporation marks sites of UV repair in human cells. Cell 127, 481–493 (2006)

    Article  CAS  PubMed  Google Scholar 

  30. Linger, J. & Tyler, J. K. The yeast histone chaperone chromatin assembly factor 1 protects against double-strand DNA-damaging agents. Genetics 171, 1513–1522 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank N. Miller for technical assistance and expertise with FACS sorting and S. Jackson for stimulating discussions and critical reading of the manuscript. Additionally, we thank D. Tremethick, P. Adams and T. Jenuwein for sharing their antibodies. K.A. was a recipient of a Marie Curie and a Newton Trust fellowships, F.C. was a holder of a Marie Curie Fellowship and U.C.L. was supported by a Wellcome Trust PhD studentship. This work was funded by grants from the Wellcome Trust to M.A.S.

Author Contributions P.H. designed and performed the experiments and analysed the data. K.A. performed the analysis of chromatin in early PGCs. T.W., N.L., G.A. and R.S. were involved in the histone variant studies. U.C.L., F.C. and C.L. helped to prepare the samples for cryosectioning and FACS sorting. G.A. and R.S. contributed to experimental design. M.A.S. was involved in the experimental design and, together with P.H., wrote the paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Azim Surani.

Additional information

One of the authors, F.C., was temporarily on the staff at Nature while the manuscript was being reviewed, but was not in any way involved in this process.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-13 with Legends and Supplementary Methods. (PDF 4813 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hajkova, P., Ancelin, K., Waldmann, T. et al. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452, 877–881 (2008). https://doi.org/10.1038/nature06714

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06714

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

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