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Histone arginine methylation regulates pluripotency in the early mouse embryo


It has been generally accepted that the mammalian embryo starts its development with all cells identical, and only when inside and outside cells form do differences between cells first emerge. However, recent findings show that cells in the mouse embryo can differ in their developmental fate and potency as early as the four-cell stage1,2,3,4. These differences depend on the orientation and order of the cleavage divisions that generated them2,5. Because epigenetic marks are suggested to be involved in sustaining pluripotency6,7, we considered that such developmental properties might be achieved through epigenetic mechanisms. Here we show that modification of histone H3, through the methylation of specific arginine residues, is correlated with cell fate and potency. Levels of H3 methylation at specific arginine residues are maximal in four-cell blastomeres that will contribute to the inner cell mass (ICM) and polar trophectoderm and undertake full development when combined together in chimaeras. Arginine methylation of H3 is minimal in cells whose progeny contributes more to the mural trophectoderm and that show compromised development when combined in chimaeras. This suggests that higher levels of H3 arginine methylation predispose blastomeres to contribute to the pluripotent cells of the ICM. We confirm this prediction by overexpressing the H3-specific arginine methyltransferase CARM1 in individual blastomeres and show that this directs their progeny to the ICM and results in a dramatic upregulation of Nanog and Sox2. Thus, our results identify specific histone modifications as the earliest known epigenetic marker contributing to development of ICM and show that manipulation of epigenetic information influences cell fate determination.

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Figure 1: Levels of H3R26me are different in blastomeres of four-cell-stage embryos and correlate with their spatial arrangement.
Figure 2: The ‘vegetal’ blastomere in ME embryos has the lowest levels of H3R26me.
Figure 3: CARM1 overexpression in a two-cell blastomere results in the contribution of that cell predominantly to the ICM.
Figure 4: Overexpression of CARM1 results in elevated levels of arginine methylation and upregulation of Nanog and Sox2.


  1. Piotrowska, K., Wianny, F., Pedersen, R. A. & Zernicka-Goetz, M. Blastomeres arising from the first cleavage division have distinguishable fates in normal mouse development. Development 128, 3739–3748 (2001)

    CAS  PubMed  Google Scholar 

  2. Piotrowska-Nitsche, K., Perea-Gomez, A., Haraguchi, S. & Zernicka-Goetz, M. Four-cell stage mouse blastomeres have different developmental properties. Development 132, 479–490 (2005)

    CAS  Article  Google Scholar 

  3. Gardner, R. L. Specification of embryonic axes begins before cleavage in normal mouse development. Development 128, 839–847 (2001)

    CAS  PubMed  Google Scholar 

  4. Fujimori, T., Kurotaki, Y., Miyazaki, J. & Nabeshima, Y. Analysis of cell lineage in two- and four-cell mouse embryos. Development 130, 5113–5122 (2003)

    CAS  Article  Google Scholar 

  5. Piotrowska-Nitsche, K. & Zernicka-Goetz, M. Spatial arrangement of individual 4-cell stage blastomeres and the order in which they are generated correlate with blastocyst pattern in the mouse embryo. Mech. Dev. 122, 487–500 (2005)

    CAS  Article  Google Scholar 

  6. Li, E. Chromatin modification and epigenetic reprogramming in mammalian development. Nature Rev. Genet. 3, 662–673 (2002)

    CAS  Article  Google Scholar 

  7. Morgan, H. D., Santos, F., Green, K., Dean, W. & Reik, W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14 (Spec. Iss. 1). R47–R58 (2005)

    CAS  Article  Google Scholar 

  8. Chen, D. et al. Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 (1999)

    CAS  Article  Google Scholar 

  9. Ma, H. et al. Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr. Biol. 11, 1981–1985 (2001)

    CAS  Article  Google Scholar 

  10. Bauer, U. M., Daujat, S., Nielsen, S. J., Nightingale, K. & Kouzarides, T. Methylation at arginine 17 of histone H3 is linked to gene activation. EMBO Rep. 3, 39–44 (2002)

    CAS  Article  Google Scholar 

  11. Gardner, R. L. Experimental analysis of second cleavage in the mouse. Hum. Reprod. 17, 3178–3189 (2002)

    CAS  Article  Google Scholar 

  12. Bannister, A. J. & Kouzarides, T. Reversing histone methylation. Nature 436, 1103–1106 (2005)

    ADS  CAS  Article  Google Scholar 

  13. Schurter, B. T. et al. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry 40, 5747–5756 (2001)

    CAS  Article  Google Scholar 

  14. Wang, H. et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293, 853–857 (2001)

    ADS  CAS  Article  Google Scholar 

  15. Strahl, B. D. et al. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr. Biol. 11, 996–1000 (2001)

    CAS  Article  Google Scholar 

  16. Lee, Y. H., Koh, S. S., Zhang, X., Cheng, X. & Stallcup, M. R. Synergy among nuclear receptor coactivators: selective requirement for protein methyltransferase and acetyltransferase activities. Mol. Cell. Biol. 22, 3621–3632 (2002)

    CAS  Article  Google Scholar 

  17. Scholer, H. R., Hatzopoulos, A. K., Balling, R., Suzuki, N. & Gruss, P. A family of octamer-specific proteins present during mouse embryogenesis: evidence for germline-specific expression of an Oct factor. EMBO J. 8, 2543–2550 (1989)

    CAS  Article  Google Scholar 

  18. Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003)

    CAS  Article  Google Scholar 

  19. Deb, K., Sivaguru, M., Yong, H. Y. & Roberts, R. M. Cdx2 gene expression and trophectoderm lineage specification in mouse embryos. Science 311, 992–996 (2006)

    ADS  CAS  Article  Google Scholar 

  20. Mitsui, K. et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631–642 (2003)

    CAS  Article  Google Scholar 

  21. Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655 (2003)

    CAS  Article  Google Scholar 

  22. Meshorer, E. et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10, 105–116 (2006)

    CAS  Article  Google Scholar 

  23. Torres-Padilla, M. E. & Zernicka-Goetz, M. Role of TIF1α as a modulator of embryonic transcription in the mouse zygote. J. Cell Biol. 174, 329–338 (2006)

    CAS  Article  Google Scholar 

  24. Tassy, O., Daian, F., Hudson, C., Bertrand, V. & Lemaire, P. A quantitative approach to the study of cell shapes and interactions during early chordate embryogenesis. Curr. Biol. 16, 345–358 (2006)

    CAS  Article  Google Scholar 

  25. Cheng, D. et al. Small molecule regulators of protein arginine methyltransferases. J. Biol. Chem. 279, 23892–23899 (2004)

    CAS  Article  Google Scholar 

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We thank P. Greda for bead labelling, C. Lee for assistance, D. Glover for comments on the manuscript, M. Stallcup for the CARM1 expression vectors, and M. Bedford for providing the Carm1-/- MEFs and the PRMT inhibitor. M.-E.T.-P. is an EMBO long-term fellow. We are grateful to the Wellcome Trust Senior Fellowship to M.Z.-G., which supported this work.

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Correspondence to Magdalena Zernicka-Goetz.

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Torres-Padilla, ME., Parfitt, DE., Kouzarides, T. et al. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445, 214–218 (2007).

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