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PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos

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Abstract

In eukaryotes, Suv39h H3K9 trimethyltransferases are required for pericentric heterochromatin formation and function. In early mouse preimplantation embryos, however, paternal pericentric heterochromatin lacks Suv39h-mediated H3K9me3 and downstream marks. Here we demonstrate Ezh2-independent targeting of maternally provided polycomb repressive complex 1 (PRC1) components to paternal heterochromatin. In Suv39h2 maternally deficient zygotes, PRC1 also associates with maternal heterochromatin lacking H3K9me3, thereby revealing hierarchy between repressive pathways. In Rnf2 maternally deficient zygotes, the PRC1 complex is disrupted, and levels of pericentric major satellite transcripts are increased at the paternal but not the maternal genome. We conclude that in early embryos, Suv39h-mediated H3K9me3 constitutes the dominant maternal transgenerational signal for pericentric heterochromatin formation. In absence of this signal, PRC1 functions as the default repressive back-up mechanism. Parental epigenetic asymmetry, also observed along cleavage chromosomes, is resolved by the end of the 8-cell stage—concurrent with blastomere polarization—marking the end of the maternal-to-embryonic transition.

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Figure 1: Maternal and paternal heterochromatin are marked by distinct repressive complexes in preimplantation embryos.
Figure 2: Differential heterochromatic states are maintained up to the 8-cell stage in a parental origin–dependent manner.
Figure 3: PRC1 components are targeted to chromatin upon gamete fusion.
Figure 4: Maternally provided Rnf2 is targeted to paternal constitutive heterochromatin and euchromatin.
Figure 5: Heterochromatic but not euchromatic matPRC1 targeting is Ezh2 independent.(a) Immunofluorescence analysis of germinal vesicle and M-II oocytes and PN0 zygotes shows that after gamete fusion (PN0), Ezh2 preferentially accumulates at the maternal genome complement that will constitute the embryo (bottom; arrow).
Figure 6: Parent of origin–specific labeling of constitutive heterochromatin and chromosome arms by Rnf2 and H3K9me3.
Figure 7: Absence of H3K9me3 and HP1β allows matPRC1 targeting to constitutive heterochromatin in early embryos.
Figure 8: MatPRC1 is required for transcriptional repression of major satellites on the paternal genome in early embryos.

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Change history

  • 16 March 2008

    In the version of this article initially published online, the text in green associated with the right-most panel in Figure 1c should read ‘H3K27me3’, not ’H3K9me3’. The error has been corrected for all versions of the article.

References

  1. Surani, M.A., Hayashi, K. & Hajkova, P. Genetic and epigenetic regulators of pluripotency. Cell 128, 747–762 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Arney, K.L., Bao, S., Bannister, A.J., Kouzarides, T. & Surani, M.A. Histone methylation defines epigenetic asymmetry in the mouse zygote. Int. J. Dev. Biol. 46, 317–320 (2002).

    CAS  PubMed  Google Scholar 

  3. Dean, W. et al. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc. Natl. Acad. Sci. USA 98, 13734–13738 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Govin, J. et al. Pericentric heterochromatin reprogramming by new histone variants during mouse spermiogenesis. J. Cell Biol. 176, 283–294 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu, H., Kim, J.M. & Aoki, F. Regulation of histone H3 lysine 9 methylation in oocytes and early pre-implantation embryos. Development 131, 2269–2280 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Martin, C. et al. Genome restructuring in mouse embryos during reprogramming and early development. Dev. Biol. 292, 317–332 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  8. van der Heijden, G.W. et al. Transmission of modified nucleosomes from the mouse male germline to the zygote and subsequent remodeling of paternal chromatin. Dev. Biol. 298, 458–469 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. van der Heijden, G.W. et al. Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote. Mech. Dev. 122, 1008–1022 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Merico, V. et al. Epigenomic differentiation in mouse preimplantation nuclei of biparental, parthenote and cloned embryos. Chromosome Res. 15, 341–360 (2007).

    CAS  PubMed  Google Scholar 

  11. Kishigami, S. et al. Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids. Dev. Biol. 289, 195–205 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Ekwall, K. et al. Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function. J. Cell Sci. 109, 2637–2648 (1996).

    CAS  PubMed  Google Scholar 

  13. Peters, A.H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Peters, A.H. & Schubeler, D. Methylation of histones: playing memory with DNA. Curr. Opin. Cell Biol. 17, 230–238 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Wustmann, G., Szidonya, J., Taubert, H. & Reuter, G. The genetics of position-effect variegation modifying loci in Drosophila melanogaster. Mol. Gen. Genet. 217, 520–527 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Grewal, S.I. & Jia, S. Heterochromatin revisited. Nat. Rev. Genet. 8, 35–46 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Schotta, G. et al. A silencing pathway to induce H3–K9 and H4–K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Schwartz, Y.B. & Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nat. Rev. Genet. 8, 9–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Levine, S.S., King, I.F. & Kingston, R.E. Division of labor in polycomb group repression. Trends Biochem. Sci. 29, 478–485 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer 6, 846–856 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Boyer, L.A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Bernstein, E. et al. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol. Cell. Biol. 26, 2560–2569 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fujimura, Y. et al. Distinct roles of Polycomb group gene products in transcriptionally repressed and active domains of Hoxb8. Development 133, 2371–2381 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Guenatri, M., Bailly, D., Maison, C. & Almouzni, G. Mouse centric and pericentric satellite repeats form distinct functional heterochromatin. J. Cell Biol. 166, 493–505 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Probst, A.V., Santos, F., Reik, W., Almouzni, G. & Dean, W. Structural differences in centromeric heterochromatin are spatially reconciled on fertilisation in the mouse zygote. Chromosoma 116, 403–415 (2007).

    Article  PubMed  Google Scholar 

  31. Peters, A.H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Mayer, W., Smith, A., Fundele, R. & Haaf, T. Spatial separation of parental genomes in preimplantation mouse embryos. J. Cell Biol. 148, 629–634 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. O'Carroll, D. et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Leeb, M. & Wutz, A. Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells. J. Cell Biol. 178, 219–229 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baxter, J. et al. Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes. EMBO J. 23, 4462–4472 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Voncken, J.W. et al. Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc. Natl. Acad. Sci. USA 100, 2468–2473 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Lu, J. & Gilbert, D.M. Proliferation-dependent and cell cycle regulated transcription of mouse pericentric heterochromatin. J. Cell Biol. 179, 411–421 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aoki, F., Worrad, D.M. & Schultz, R.M. Regulation of transcriptional activity during the first and second cell cycles in the preimplantation mouse embryo. Dev. Biol. 181, 296–307 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Rudolph, T. et al. Heterochromatin formation in Drosophila is initiated through active removal of H3K4 methylation by the LSD1 homolog SU(VAR)3–3. Mol. Cell 26, 103–115 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Sun, F. et al. Nuclear reprogramming: the zygotic transcription program is established through an “erase-and-rebuild” strategy. Cell Res. 17, 117–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Yoshida, N., Brahmajosyula, M., Shoji, S., Amanai, M. & Perry, A.C. Epigenetic discrimination by mouse metaphase II oocytes mediates asymmetric chromatin remodeling independently of meiotic exit. Dev. Biol. 301, 464–477 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Schoeftner, S. et al. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. EMBO J. 25, 3110–3122 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Umlauf, D. et al. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat. Genet. 36, 1296–1300 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Maison, C. et al. Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nat. Genet. 30, 329–334 (2002).

    Article  PubMed  Google Scholar 

  46. Chong, S. et al. Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat. Genet. 39, 614–622 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Johnson, M.H. Manipulation of early mammalian development: what does it tell us about cell lineages? Dev Biol (N Y 1985) 4, 279–96 (1986).

    CAS  Google Scholar 

  48. Okamoto, I., Otte, A.P., Allis, C.D., Reinberg, D. & Heard, E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303, 644–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Blewitt, M.E., Vickaryous, N.K., Paldi, A., Koseki, H. & Whitelaw, E. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2, e49 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Vidal (Centro de Investigaciones Biológicas, Spain) and T. Jenuwein (Research Institute of Molecular Pathology, Austria) for providing antisera. Moreover, we are grateful to T. Jenuwein and B. Knowles (The Jackson Laboratory, USA) for providing Suv39h2 deficient and Zp3-cre transgenic mice, respectively. We acknowledge excellent assistance by Friedrich Miescher Institute (FMI) colleagues P. Schwarb and J. Rietdorf (microscopy and imaging facility), B. Heller-Stilb and J.-F. Spetz (animal facility), S. Bichet (histology) and M. Stadler (bioinformatics). We thank members of the Peters laboratory for fruitful discussions and P. de Boer, D. Schübeler, S. Gasser and P. Hublitz for valuable comments on the manuscript. Research at the Friedrich Miescher Institute is supported by the Novartis Research Foundation. M.P. acknowledges the Boehringer Ingelheim Fonds for her PhD fellowship. Research in the Peters laboratory is supported by the EU NoE network 'The Epigenome' (LSHG-CT-2004-503433).

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M.P. and A.H.F.M.P. conceived and designed the experiments. M.P., R.T., U.B. and C.K. performed the experiments. M.P., R.T., U.B. and A.H.F.M.P. analyzed the data. A.P.O. provided antibodies. E.B. and M.v.L. provided conditionally deficient Rnf2 mice. X.M. and S.H.O. provided conditionally deficient Ezh2 mice. K.I. and H.K. provided Rnf2–YFP knock-in mice. M.P. and A.H.F.M.P. wrote the manuscript.

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Correspondence to Antoine H F M Peters.

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Puschendorf, M., Terranova, R., Boutsma, E. et al. PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nat Genet 40, 411–420 (2008). https://doi.org/10.1038/ng.99

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