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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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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This file contains technical details of experimental methods used in this study. (DOC 25 kb)
GST pull-down mapping the interaction between DNMTs and EZH2. (PDF 3367 kb)
EED and SUZ12 associate with DNA methyltransferase activity. (PDF 3610 kb)
Validation of depletion of endogenous EZH2 or DNMTs by RNAi. (PDF 2998 kb)
EZH2 or H3K27me3 binding to MYT1 does not require the presence of DNMTs. (PDF 3031 kb)
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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