Letter | Published:

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

Nature volume 464, pages 306310 (11 March 2010) | Download Citation

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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

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

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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.

Author information

Author notes

    • Diego Pasini

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

    • Paul A. C. Cloos
    •  & Julian Walfridsson

    These authors contributed equally to this work.

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. Wilhelm Johannsen Centre For Functional Genome Research, Department of Cellular and Molecular Medicine, 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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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.

Corresponding author

Correspondence to Kristian Helin.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figures S1-S11 with Legends.

Excel files

  1. 1.

    Supplementary Table 1

    This table contains the chromosomal coordinates of the peaks and the target genes lists of the ChIP-seq experiments.

  2. 2.

    Supplementary Table 2

    This table contains the results of the expression arrays of the ES cells differentiation experiment.

  3. 3.

    Supplementary Table 3

    This table contains the primer sequences for real-time quantitative PCR and the list of the used antibodies.

About this article

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DOI

https://doi.org/10.1038/nature08788

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