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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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.
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.
This file contains Supplementary Figures S1-S11 with Legends. (PDF 2348 kb)
This table contains the chromosomal coordinates of the peaks and the target genes lists of the ChIP-seq experiments. (XLS 2162 kb)
This table contains the results of the expression arrays of the ES cells differentiation experiment. (XLS 8272 kb)
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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