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JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells

Nature volume 464, pages 306–310 (2010)Cite this article

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Abstract

The Polycomb group (PcG) proteins have an important role in controlling the expression of genes essential for development, differentiation and maintenance of cell fates1,2. The Polycomb repressive complex 2 (PRC2) is believed to regulate transcriptional repression by catalysing the di- and tri-methylation of lysine 27 on histone H3 (H3K27me2/3)2. At present, it is unknown how the PcG proteins are recruited to their target promoters in mammalian cells3. Here we show that PRC2 forms a stable complex with the Jumonji- and ARID-domain-containing protein, JARID2 (ref. 4). Using genome-wide location analysis, we show that JARID2 binds to more than 90% of previously mapped PcG target genes. Notably, we show that JARID2 is sufficient to recruit PcG proteins to a heterologous promoter, and that inhibition of JARID2 expression leads to a major loss of PcG binding and to a reduction of H3K27me3 levels on target genes. Consistent with an essential role for PcG proteins in early development5,6,7,8, we demonstrate that JARID2 is required for the differentiation of mouse embryonic stem cells. Thus, these results demonstrate that JARID2 is essential for the binding of PcG proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development.

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Figure 1: JARID2 is a component of the PRC2 complex.
Figure 2: JARID2-mediated transcriptional repression is dependent on PRC2 binding.
Figure 3: JARID2 and PRC2 associate with a very similar set of genes in ES cells.
Figure 4: Jarid2 is required for ES cell differentiation.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

ChIP-seq data are available at the Gene Expression Omnibus (GEO) under accession GSE19365.

References

  1. Schuettengruber, B., Chourrout, D., Vervoort, M., Leblanc, B. & Cavalli, G. Genome regulation by polycomb and trithorax proteins. Cell 128, 735–745 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Bracken, A. P. & Helin, K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nature Rev. Cancer 9, 773–784 (2009)

    Article  CAS  Google Scholar 

  4. Takeuchi, T., Kojima, M., Nakajima, K. & Kondo, S. jumonji gene is essential for the neurulation and cardiac development of mouse embryos with a C3H/He background. Mech. Dev. 86, 29–38 (1999)

    Article  CAS  Google Scholar 

  5. Faust, C., Lawson, K. A., Schork, N. J., Thiel, B. & Magnuson, T. The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo. Development 125, 4495–4506 (1998)

    CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  7. 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 

  8. 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  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  10. Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006)

    Article  CAS  Google Scholar 

  11. Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006)

    Article  CAS  Google Scholar 

  12. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Cao, R., Tsukada, Y. & Zhang, Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845–854 (2005)

    Article  CAS  Google Scholar 

  14. 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 

  15. Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002)

    Article  CAS  Google Scholar 

  16. Müller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002)

    Article  Google Scholar 

  17. Kim, T. G., Kraus, J. C., Chen, J. & Lee, Y. JUMONJI, a critical factor for cardiac development, functions as a transcriptional repressor. J. Biol. Chem. 278, 42247–42255 (2003)

    Article  CAS  Google Scholar 

  18. Cloos, P. A., Christensen, J., Agger, K. & Helin, K. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22, 1115–1140 (2008)

    Article  CAS  Google Scholar 

  19. Takeuchi, T. et al. Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation. Genes Dev. 9, 1211–1222 (1995)

    Article  CAS  Google Scholar 

  20. Kim, T. G., Chen, J., Sadoshima, J. & Lee, Y. Jumonji represses atrial natriuretic factor gene expression by inhibiting transcriptional activities of cardiac transcription factors. Mol. Cell. Biol. 24, 10151–10160 (2004)

    Article  CAS  Google Scholar 

  21. Ku, M. et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet. 4, e1000242 (2008)

    Article  Google Scholar 

  22. Pasini, D., Bracken, A. P., Hansen, J. B., Capillo, M. & Helin, K. The Polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol. Cell. Biol. 27, 3769–3779 (2007)

    Article  CAS  Google Scholar 

  23. Chamberlain, S. J., Yee, D. & Magnuson, T. Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells 26, 1496–1505 (2008)

    Article  CAS  Google Scholar 

  24. Shen, X. et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol. Cell 32, 491–502 (2008)

    Article  MathSciNet  CAS  Google Scholar 

  25. Pasini, D. et al. Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harb. Symp. Quant. Biol. 73, 253–263 (2008)

    Article  CAS  Google Scholar 

  26. Hansen, K. H. et al. A model for transmission of the H3K27me3 epigenetic mark. Nature Cell Biol. 10, 1291–1300 (2008)

    Article  CAS  Google Scholar 

  27. Margueron, R. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009)

    Article  ADS  CAS  Google Scholar 

  28. Pasini, D. et al. Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev. 22, 1345–1355 (2008)

    Article  CAS  Google Scholar 

  29. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    Article  ADS  CAS  Google Scholar 

  30. Villa, R. et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer Cell 11, 513–525 (2007)

    Article  CAS  Google Scholar 

  31. Christensen, J. et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076 (2007)

    Article  CAS  Google Scholar 

  32. Wilm, M. et al. Femtomole sequencing of proteins from polyacrylamide gels by nano-electrospray mass spectrometry. Nature 379, 466–469 (1996)

    Article  ADS  CAS  Google Scholar 

  33. Ji, H. et al. An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nature Biotechnol. 26, 1293–1300 (2008)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Hansen for the RING1B antibody, J. Vikesaa for bioinformatics support, and F. de Lima Alves for assistance during mass spectrometry analyses. We thank L. Morey for critical reading of the manuscript, and members of the Helin laboratory for discussions, technical advice and support. D.P. was supported by a post-doctoral fellowship from the Danish Medical Research Council, P.A.C.C. by a grant from the Benzon Foundation and J.W. by a post-doctoral fellowship from NordForsk (Nordic Union). J.R. is a Senior Research Fellow of the Wellcome Trust. The Wilhelm Johannsen Center is supported by the Danish National Research Foundation and the Lundbeck Foundation. The work in the Helin laboratory was supported by grants from the Danish National Research Foundation, the Danish Cancer Society, the Novo Nordisk Foundation, the Danish Medical Research Council, and the Danish Natural Science Research Council.

Author Contributions D.P. and K.H. conceived and designed the project. D.P. performed experiments in Figs 1a, c, d, 2a, 3 and 4 and Supplementary Figs 1a, c–f, 2a, b, 3b and 4–9. P.A.C.C. designed and performed the experiments in Fig. 1b and Supplementary Figs 1b and 3a. J.W. performed experiments in Fig. 2b–d, Supplementary Figs 2c and 3a. J.-P.B. cloned JARID2. L.O. provided technical support. M.B. and N.T. performed the Solexa sequencing. J.R. performed mass spectrometry analyses. J.V.J. provided bioinformatics support. D.P. and K.H. wrote the manuscript.

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Author notes

  1. Diego Pasini

    Present address: Present address: European Institute of Oncology, Department of Experimental Oncology, Via Adamello 16, 20141 Milan, Italy.,

  2. Paul A. C. Cloos and Julian Walfridsson: These authors contributed equally to this work.

Authors and Affiliations

  1. Biotech Research and Innovation Centre (BRIC),,

    Diego Pasini, Paul A. C. Cloos, Julian Walfridsson, Linda Olsson, John-Paul Bukowski, Jens V. Johansen & Kristian Helin

  2. Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark ,

    Diego Pasini, Paul A. C. Cloos, Julian Walfridsson, Linda Olsson, John-Paul Bukowski & Kristian Helin

  3. Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre For Functional Genome Research, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark,

    Mads Bak & Niels Tommerup

  4. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK

    Juri Rappsilber

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Corresponding author

Correspondence to Kristian Helin.

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Competing interests

K.H. and P.A.C.C. are cofounders of EpiTherapeutics and have shares and warrants in the company. All other authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S11 with Legends. (PDF 2348 kb)

Supplementary Table 1

This table contains the chromosomal coordinates of the peaks and the target genes lists of the ChIP-seq experiments. (XLS 2162 kb)

Supplementary Table 2

This table contains the results of the expression arrays of the ES cells differentiation experiment. (XLS 8272 kb)

Supplementary Table 3

This table contains the primer sequences for real-time quantitative PCR and the list of the used antibodies. (XLS 28 kb)

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Pasini, D., Cloos, P., Walfridsson, J. et al. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306–310 (2010). https://doi.org/10.1038/nature08788

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