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) proteins^{2, 3} and the DNA methylation^{4, 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.

1. Free University of Brussels, Faculty of Medicine, Laboratory of Molecular Virology, 808 route de Lennik, 1070 Brussels, Belgium
2. CNIO, Cancer Epigenetics Group, C/- Melchor Fernández Almagro 3, 28029 Madrid, Spain
3. ICREA and CRG, Passeig Maritim 37-49, E-08003 Barcelona, Spain
4. Division of Biochemistry, Faculteit Geneeskunde, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium
5. Free University of Brussels, Faculty of Medicine, Laboratory of Neurophysiology, 808 route de Lennik, 1070 Brussels, Belgium
6. UMR 8117, CNRS, Institut Pasteur de Lille, Université de Lille 1, Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille, Cedex, France

Correspondence to: François Fuks¹ Correspondence and requests for materials should be addressed to F.F. (Email: ffuks@ulb.ac.be).

Received 6 October 2005; Accepted 15 November 2005

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