Oct-3/4 is a POU domain homeobox gene that is expressed during gametogenesis and in early embryonic cells1,2, where it has been shown to be important for maintaining pluripotency3. Following implantation, this gene undergoes a novel multi-step programme of inactivation. Transcriptional repression is followed by a pronounced increase in histone H3 methylation on Lys 9 that is mediated by the SET-containing protein, G9a. This step sets the stage for local heterochromatinization via the binding of HP1 and is required for subsequent de novo methylation at the promoter by the enzymes Dnmt3a/3b. Genetic studies show that these epigenetic changes actually have an important role in the inhibition of Oct-3/4 re-expression, thereby preventing reprogramming.
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Brehm, A., Ovitt, C. E. & Scholer, H. R. Oct-4: more than just a POUerful marker of the mammalian germline? Apmis 106, 114–126 (1998).
Pesce, M. & Scholer, H. R. Oct-4: control of totipotency and germline determination. Mol. Reprod. Dev. 55, 452–457 (2000).
Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).
Pikarsky, E., Sharir, H., Ben-Shushan, E. & Bergman, Y. Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol. Cell. Biol. 14, 1026–1038 (1994).
Okamoto, K. et al. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 60, 461–472 (1990).
Ben-Shushan, E., Sharir, H., Pikarsky, E. & Bergman, Y. A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells. Mol. Cell. Biol. 15, 1034–1048 (1995).
Fuhrmann, G. et al. Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev. Cell 1, 377–387 (2001).
Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).
Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell. Biol. 14, 286–298 (2002).
Kimura, H., Tada, M., Nakatsuji, N. & Tada, T. Histone code modifications on pluripotential nuclei of reprogrammed somatic cells. Mol. Cell. Biol. 24, 5710–5720 (2004).
Gidekel, S. & Bergman, Y. A unique developmental pattern of Oct-3/4 DNA methylation is controlled by a cis-demodification element. J. Biol. Chem. 277, 34521–34530 (2002).
Brandeis, M. et al. Sp1 elements protect a CpG island from de novo methylation. Nature 371, 435–438 (1994).
Ben-Shushan, E., Thompson, J. R., Gudas, L. J. & Bergman, Y. Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site. Mol. Cell. Biol. 18, 1866–1878 (1998).
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
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).
Stewart, M. D., Li, J. & Wong, J. Relationship between histone H3 lysine 9 methylation, transcription repression, and heterochromatin protein 1 recruitment. Mol. Cell. Biol. 25, 2525–2538 (2005).
Osipovich, O. et al. Targeted inhibition of V(D)J recombination by a histone methyltransferase. Nature Immunol. 5, 309–316 (2004).
Freitag, M. & Selker, E. U. Controlling DNA methylation: many roads to one modification. Curr. Opin. Genet. Dev. 15, 191–199 (2005).
Tachibana, M. et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815–826 (2005).
Ayyanathan, K. et al. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 17, 1855–1869 (2003).
Fahrner, J. A. & Baylin, S. B. Heterochromatin: stable and unstable invasions at home and abroad. Genes Dev. 17, 1805–1812 (2003).
Goldmit, M. et al. Epigenetic ontogeny of the k locus during B cell development. Nature Immunol. 6, 198–203 (2005).
Boiani, M., Eckardt, S., Scholer, H. R. & McLaughlin, K. J. Oct4 distribution and level in mouse clones: consequences for pluripotency. Genes Dev. 16, 1209–1219 (2002).
Bortvin, A. et al. Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development 130, 1673–1680 (2003).
Simonsson, S. & Gurdon, J. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nature Cell Biol. 6, 984–990 (2004).
Jorgensen, H. F., Ben-Porath, I. & Bird, A. P. Mbd1 is recruited to both methylated and nonmethylated CpGs via distinct DNA binding domains. Mol. Cell. Biol. 24, 3387–3395 (2004).
Ji, Y., Zhang, J., Lee, A. I., Cedar, H. & Bergman, Y. A multistep mechanism for the activation of rearrangement in the immune system. Proc. Natl Acad. Sci. USA 100, 7557–7562 (2003).
Tachibana, M., Sugimoto, K., Fukushima, T. & Shinkai, Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).
Hattori, N. et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J. Biol. Chem. 279, 17063–17069 (2004).
Fuks, F., Hurd, P. J., Deplus, R. & Kouzarides, T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 31, 2305–2312 (2003).
We are grateful to T. Jenuwein for his cooperation. This work was supported by grants from the Israel Academy of Sciences (Y.B. and H.C.), Philip Morris USA Inc. and Philip Morris International (Y.B. and H.C), the National Institutes of Health (Y.Z., Y.B. and H.C.), the European Community 5th Framework Quality of Life Program (Y.B.), The American Cancer Society (Y.Z.), the Israel Cancer Research Fund (H.C.) and the Prostate Cancer Foundation (H.C.).
The authors declare no competing financial interests.
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