Movatterモバイル変換

[0]ホーム
URL:

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.

Advertisement

Nature
  • Letter
  • Published:

Polycomb complexes repress developmental regulators in murine embryonic stem cells

Naturevolume 441, pages349–353 (2006)Cite this article

Abstract

The mechanisms by which embryonic stem (ES) cells self-renew while maintaining the ability to differentiate into virtually all adult cell types are not well understood. Polycomb group (PcG) proteins are transcriptional repressors that help to maintain cellular identity during metazoan development by epigenetic modification of chromatin structure1. PcG proteins have essential roles in early embryonic development2,3,4,5,6 and have been implicated in ES cell pluripotency2, but few of their target genes are known in mammals. Here we show that PcG proteins directly repress a large cohort of developmental regulators in murine ES cells, the expression of which would otherwise promote differentiation. Using genome-wide location analysis in murine ES cells, we found that the Polycomb repressive complexes PRC1 and PRC2 co-occupied 512 genes, many of which encode transcription factors with important roles in development. All of the co-occupied genes contained modified nucleosomes (trimethylated Lys 27 on histone H3). Consistent with a causal role in gene silencing in ES cells, PcG target genes were de-repressed in cells deficient for the PRC2 component Eed, and were preferentially activated on induction of differentiation. Our results indicate that dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development.

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

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

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

Figure 1:PRC1 and PRC2 colocalize at genes encoding developmental regulators.
Figure 2:De-repression of PcG target genes and loss of PRC1 binding in the absence of the PRC2 component Eed.
Figure 3:PcG target genes are preferentially upregulated during ES cell differentiation.

Similar content being viewed by others

References

  1. 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  Google Scholar 

  2. O'Carroll, D. et al. ThePolycomb-group geneEzh2 is required for early mouse development.Mol. Cell. Biol.21, 4330–4336 (2001)

    Article CAS  Google Scholar 

  3. Pasini, D., Bracken, A. P., Jensen, M. R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity.EMBO J.23, 4061–4071 (2004)

    Article CAS  Google Scholar 

  4. Shumacher, A., Faust, C. & Magnuson, T. Positional cloning of a global regulator of anterior–posterior patterning in mice.Nature383, 250–253 (1996)

    Article ADS CAS  Google Scholar 

  5. Voncken, J. W. et al.Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition.Proc. Natl Acad. Sci. USA100, 2468–2473 (2003)

    Article ADS CAS  Google Scholar 

  6. Isono, K. et al. Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression ofHox genes.Mol. Cell. Biol.25, 6694–6706 (2005)

    Article CAS  Google Scholar 

  7. Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells.Cell122, 947–956 (2005)

    Article CAS  Google Scholar 

  8. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing.Science298, 1039–1043 (2002)

    Article ADS CAS  Google Scholar 

  9. Czermin, B. et al.Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites.Cell111, 185–196 (2002)

    Article CAS  Google Scholar 

  10. Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.Genes Dev.16, 2893–2905 (2002)

    Article CAS  Google Scholar 

  11. Muller, J. et al. Histone methyltransferase activity of aDrosophila Polycomb group repressor complex.Cell111, 197–208 (2002)

    Article CAS  Google Scholar 

  12. Kirmizis, A. et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27.Genes Dev.18, 1592–1605 (2004)

    Article CAS  Google Scholar 

  13. Hombria, J. C. & Lovegrove, B. Beyond homeosis—HOX function in morphogenesis and organogenesis.Differentiation71, 461–476 (2003)

    Article  Google Scholar 

  14. Schepers, G. E., Teasdale, R. D. & Koopman, P. Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families.Dev. Cell3, 167–170 (2002)

    Article CAS  Google Scholar 

  15. Lehmann, O. J., Sowden, J. C., Carlsson, P., Jordan, T. & Bhattacharya, S. S. Fox's in development and disease.Trends Genet.19, 339–344 (2003)

    Article CAS  Google Scholar 

  16. Showell, C., Binder, O. & Conlon, F. L. T-box genes in early embryogenesis.Dev. Dyn.229, 201–218 (2004)

    Article CAS  Google Scholar 

  17. Burch, J. B. Regulation of GATA gene expression during vertebrate development.Semin. Cell Dev. Biol.16, 71–81 (2005)

    Article CAS  Google Scholar 

  18. Montgomery, N. D. et al. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation.Curr. Biol.15, 942–947 (2005)

    Article CAS  Google Scholar 

  19. Cao, R., Tsukada, Y. & Zhang, Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing.Mol. Cell20, 845–854 (2005)

    Article CAS  Google Scholar 

  20. Gidekel, S. & Bergman, Y. A unique developmental pattern ofOct-3/4 DNA methylation is controlled by acis-demodification element.J. Biol. Chem.277, 34521–34530 (2002)

    Article CAS  Google Scholar 

  21. Hattori, N. et al. Epigenetic control of mouseOct-4 gene expression in embryonic stem cells and trophoblast stem cells.J. Biol. Chem.279, 17063–17069 (2004)

    Article CAS  Google Scholar 

  22. Feldman, N. et al. G9a-mediated irreversible epigenetic inactivation ofOct-3/4 during early embryogenesis.Nature Cell Biol.8, 188–194 (2006)

    Article CAS  Google Scholar 

  23. Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation.Nature439, 871–874 (2006)

    Article ADS CAS  Google Scholar 

  24. Meissner, A. et al. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis.Nucleic Acids Res.33, 5868–5877 (2005)

    Article CAS  Google Scholar 

  25. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.Cell69, 915–926 (1992)

    Article CAS  Google Scholar 

  26. Lee, T. et al. Control of developmental regulators by Polycomb in human embryonic stem cells.Cell125, 1–13 (2006)

    Article  Google Scholar 

Download references

Acknowledgements

We thank Biology and Research Computing (BaRC), especially B. Yuan, T. Dicesare and T. Volkert, at the Whitehead Institute's Center for Microarray Technology, as well as E. Herbolsheimer, for computational and technical support. We also thank members of the Gifford, Young and Jaenisch laboratories for discussions and critical review of the manuscript. We are grateful to T. Magnuson for theEed mutant (17Rn5-3354SB) ES cell lines. L.A.B. was supported in part by an NIH NRSA fellowship. K.P. is a special fellow of the Leukemia and Lymphoma Society. M.W. is supported by a Human Frontiers Science Program Organization Fellowship. M.V. is supported by a grant from the Spanish Ministry of Science and Education. This work was supported in part by grants from the NIHGRI and NIGMS to R.A.Y. and from the NIH and NCI to R.J.

Author information

Author notes

  1. Kathrin Plath

    Present address: Biological Chemistry Department, David Geffen School of Medicine at UCLA, 36-133 CHS, PO Box 951737, Los Angeles, California, 90095-1737, USA

  2. Laurie A. Boyer and Kathrin Plath: *These authors contributed equally to this work

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Cambridge, 9 Cambridge Center, Massachusetts, 02142, USA

    Laurie A. Boyer, Kathrin Plath, Julia Zeitlinger, Tobias Brambrink, Lea A. Medeiros, Tong Ihn Lee, Stuart S. Levine, Marius Wernig, George W. Bell, Richard A. Young & Rudolf Jaenisch

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Lea A. Medeiros, Adriana Tajonar, Mridula K. Ray, Richard A. Young & Rudolf Jaenisch

  3. Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, 1098 SM, The Netherlands

    Arie P. Otte

  4. Developmental and Cell Biology Centro de Investigaciones Biológicas (CSIC), Madrid, 28040, Spain

    Miguel Vidal

  5. Computer Science and Artificial Intelligence Laboratories, Massachusetts Institute of Technology, 32 Vassar Street, Cambridge, Massachusetts, 02139, USA

    David K. Gifford

Authors
  1. Laurie A. Boyer

    You can also search for this author inPubMed Google Scholar

  2. Kathrin Plath

    You can also search for this author inPubMed Google Scholar

  3. Julia Zeitlinger

    You can also search for this author inPubMed Google Scholar

  4. Tobias Brambrink

    You can also search for this author inPubMed Google Scholar

  5. Lea A. Medeiros

    You can also search for this author inPubMed Google Scholar

  6. Tong Ihn Lee

    You can also search for this author inPubMed Google Scholar

  7. Stuart S. Levine

    You can also search for this author inPubMed Google Scholar

  8. Marius Wernig

    You can also search for this author inPubMed Google Scholar

  9. Adriana Tajonar

    You can also search for this author inPubMed Google Scholar

  10. Mridula K. Ray

    You can also search for this author inPubMed Google Scholar

  11. George W. Bell

    You can also search for this author inPubMed Google Scholar

  12. Arie P. Otte

    You can also search for this author inPubMed Google Scholar

  13. Miguel Vidal

    You can also search for this author inPubMed Google Scholar

  14. David K. Gifford

    You can also search for this author inPubMed Google Scholar

  15. Richard A. Young

    You can also search for this author inPubMed Google Scholar

  16. Rudolf Jaenisch

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toRudolf Jaenisch.

Ethics declarations

Competing interests

T.I.L., D.K.G. and R.A.Y. consult for Agilent Technologies.

Supplementary information

Supplementary Notes

This file contains the Supplementary Methods and Supplementary Discussion; Supplementary Notes; Supplementary Figure Legends 1–9; Supplementary Figures 1–9. (PDF 9721 kb)

Supplementary Table 1

This file contains chromosomal coordinates for genomic regions bound by Suz12. (XLS 102 kb)

Supplementary Table 2

This file contains chromosomal coordinates for genomic regions bound by Eed. (XLS 69 kb)

Supplementary Table 3

This file contains chromosomal coordinates for genomic regions bound by Rnf2. (XLS 91 kb)

Supplementary Table 4

This file contains chromosomal coordinates for genomic regions bound by Phc1. (XLS 69 kb)

Supplementary Table 5

This file contains the assignment of bound genomic regions to annotated transcripts. (XLS 4189 kb)

Supplementary Table 6

This file contains data from the independent site specific validation used to estimate error rates in location analysis data. (XLS 53 kb)

Supplementary Table 7.

This file contains chromosomal coordinates for genomic regions bound by H3K27me3. (XLS 175 kb)

Supplementary Table 8

This file contains all enriched gene ontology classifications for bound genes. (XLS 103 kb)

Supplementary Table 9

This file contains the complete list of transcription factor genes bound by PcG proteins. (DOC 36 kb)

Supplementary Table 10

This file contains all oligo sequences and RT-PCR results in wild-type and eed mutant ES cells used to generate Figure 2 in the main text. (XLS 39 kb)

Supplementary Table 11

This file contains the microarray expression data used to analyse the expression of PcG bound genes in ES cells and during ES cell differentiation as displayed in Figure 3 in the main text. (XLS 6725 kb)

Rights and permissions

About this article

Cite this article

Boyer, L., Plath, K., Zeitlinger, J.et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells.Nature441, 349–353 (2006). https://doi.org/10.1038/nature04733

Download citation

This article is cited by

Access through your institution
Buy or subscribe

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature 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
[8]ページ先頭
©2009-2025 Movatter.jp