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The Polycomb group protein EZH2 directly controls DNA methylation

A Corrigendum to this article was published on 12 April 2007

Abstract

The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function1. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins2,3 and the DNA methylation4,5 systems. Here we show that the corresponding silencing pathways are mechanistically linked. We find that the PcG protein EZH2 (Enhancer of Zeste homolog 2) interacts—within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)—with DNA methyltransferases (DNMTs) and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicate that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, we show by bisulphite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Our results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems.

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Figure 1: The EZH2 Polycomb group protein associates with DNA methyltransferase activity.
Figure 2: EZH2 interacts with DNA methyltransferases in vitro and in vivo.
Figure 3: Both EZH2 and DNA methyltransferases are required to repress the endogenous MYT1 gene.
Figure 4: EZH2 is required for binding of DNA methyltransferases and facilitates CpG methylation of EZH2-target promoters.

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Acknowledgements

We thank A. Otte for pGEX-EZH2, E. Li for DNMT3A and DNMT3B immune sera, S. Pradhan for the anti-DNMT1 antibody, and C. Beaudouin for pGEX-PLZF. We thank P. Putmans and H. N. Tran for excellent technical assistance. E.V., C.B., R.D., C.D. and L.B. were supported by the Télévie and the F.N.R.S. L.B. was also supported by the “Fondation pour la Recherche Médicale”. D.B. was supported by a Marie Curie Fellowship. F.F. is a “Chercheur Qualifié du F.N.R.S.”. This work was supported by grants from MEC-Plan Nacional de I + D + I to L.D.C., and from the “Fédération Belge contre le Cancer”, the F.N.R.S, “FB Assurances”, and “A.R.C. de la Communauté Française de Belgique” to Y.d.L. and F.F.

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Correspondence to François Fuks.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

This file contains technical details of experimental methods used in this study. (DOC 25 kb)

Supplementary Figure 1

GST pull-down mapping the interaction between DNMTs and EZH2. (PDF 3367 kb)

Supplementary Figure 2

EED and SUZ12 associate with DNA methyltransferase activity. (PDF 3610 kb)

Supplementary Figure 3

Validation of depletion of endogenous EZH2 or DNMTs by RNAi. (PDF 2998 kb)

Supplementary Figure 4

EZH2 or H3K27me3 binding to MYT1 does not require the presence of DNMTs. (PDF 3031 kb)

Supplementary Figure 5

CpG methylation status analysis of the EZH2-target promoters MYT1 and WNT1 in cells overexpressing EZH2. (PDF 4661 kb)

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Viré, E., Brenner, C., Deplus, R. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006). https://doi.org/10.1038/nature04431

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