Abstract
DNA methylation is an important means of epigenetic gene regulation1,2 and must be carefully controlled as a prerequisite for normal early embryogenesis. Although global demethylation occurs soon after fertilization, it is not evenly distributed throughout the genome. Genomic imprinting and epigenetic asymmetry between parental genomes, that is, delayed demethylation of the maternal genome after fertilization3,4,5,6, are clear examples of the functional importance of DNA methylation. Here, we show that PGC7/Stella, a maternal factor essential for early development, protects the DNA methylation state of several imprinted loci and epigenetic asymmetry. After determining that PGC7/Stella binds to Ran binding protein 5 (RanBP5; a nuclear transport shuttle protein), mutant versions of the two proteins were used to examine exactly when and where PGC7/Stella functions within the cell. It is likely that PGC7/Stella protects the maternal genome from demethylation only after localizing to the nucleus, where it maintains the methylation of several imprinted genes. These results demonstrate that PGC7/Stella is indispensable for the maintenance of methylation involved in epigenetic reprogramming after fertilization.
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References
Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33, 245–254 (2003).
Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 (2000).
Oswald, J. et al. Active demethylation of the paternal genome in the mouse zygote. Curr. Biol. 10, 475–478 (2000).
Santos, F., Hendrich, B., Reik, W. & Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241, 172–182 (2002).
Santos, F. & Dean, W. Epigenetic reprogramming during early development in mammals. Reproduction 127, 643–651 (2004).
Sato, M. et al. Identification of PGC7, a new gene expressed specifically in preimplantation embryos and germ cells. Mech. Dev. 113, 91–94 (2002).
Saitou, M., Barton, S. C. & Surani, M. A. A molecular programme for the specification of germ cell fate in mice. Nature 418, 293–300 (2002).
Payer, B. et al. Stella is a maternal effect gene required for normal early development in mice. Curr. Biol. 13, 2110–2117 (2003).
Bortvin, A., Goodheart, M., Liao, M. & Page, D. C. Dppa3 / Pgc7 / stella is a maternal factor and is not required for germ cell specification in mice. BMC Dev. Biol. 4, 2 (2004).
Aravind, L. & Koonin, E. V. SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem. Sci. 25, 112–114 (2000).
Fu, X. D. & Maniatis, T. Isolation of a complementary DNA that encodes the mammalian splicing factor SC35. Science 256, 535–538 (1992).
Rigaut, G. et al. A generic protein purification method for protein complex characterization and proteome exploration. Nature Biotechnol. 17, 1030–1032 (1999).
Kikuchi, M. et al. Proteomic analysis of rat liver peroxisome: presence of peroxisome-specific isozyme of Lon protease. J. Biol. Chem. 279, 421–428 (2004).
Jakel, S. & Gorlich, D. Importin β, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells. EMBO J. 17, 4491–4502 (1998).
Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G. & Evan, G. I. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res. 23, 1686–1690 (1995).
Mayer, W., Smith, A., Fundele, R. & Haaf, T. Spatial separation of parental genomes in preimplantation mouse embryos. J. Cell Biol. 148, 629–634 (2000).
Rideout, W. M., 3rd, Eggan, K. & Jaenisch, R. Nuclear cloning and epigenetic reprogramming of the genome. Science 293, 1093–1098 (2001).
Santos, F. et al. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos. Curr. Biol. 13, 1116–1121 (2003).
Dean, W., Santos, F. & Reik, W. Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. Semin. Cell Dev. Biol. 14, 93–100 (2003).
Gurdon, J. B., Byrne, J. A. & Simonsson, S. Nuclear reprogramming and stem cell creation. Proc. Natl Acad. Sci. USA 100, 11819–11822 (2003).
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).
Reik, W. & Walter, J. Genomic imprinting: parental influence on the genome. Nature Rev. Genet. 2, 21–32 (2001).
Walsh, C. P. & Bestor, T. H. Cytosine methylation and mammalian development. Genes Dev. 13, 26–34 (1999).
Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003).
Niwa, H., Burdon, T., Chambers, I. & Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12, 2048–2060 (1998).
Olek, A., Oswald, J. & Walter, J. A modified and improved method for bisulphite based cytosine methylation analysis. Nucleic Acids Res. 24, 5064–5066 (1996).
Acknowledgements
We thank M. Sato for an initial contribution to this study, and. H. Niwa, K. Nakayama and T. A. Van Dyke for providing plasmids. We also thank Y. Fujita, M. Ikeuchi and N. Asada for assistance, and A. Mizokami for secretarial assistance. This work was supported in part by grants from the Ministry of Education, Science, Sports, Culture, and Technology; the Support Program for Technology Development on the Basis of Academic Findings (NEDO); the Uehara Memorial Foundation; the Osaka Cancer Foundation; and the 21st Century COE “CICET”.
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Nakamura, T., Arai, Y., Umehara, H. et al. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol 9, 64–71 (2007). https://doi.org/10.1038/ncb1519
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DOI: https://doi.org/10.1038/ncb1519
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