The Polycomb group protein EZH2 directly controls DNA methylation

Emmanuelle Viré; Carmen Brenner; Rachel Deplus; Loïc Blanchon; Mario Fraga; Céline Didelot; Lluis Morey; Aleyde Van Eynde; David Bernard; Jean Marie Vanderwinden; Mathieu Bollen; Manel Esteller; Luciano Di Croce; Yvan De Launoit; François Fuks

doi:10.1038/nature04431

The Polycomb group protein EZH2 directly controls DNA methylation

Emmanuelle Viré, Carmen Brenner, Rachel Deplus, Loïc Blanchon, Mario Fraga, Céline Didelot, Lluis Morey, Aleyde Van Eynde, David Bernard, Jean Marie Vanderwinden, Mathieu Bollen, Manel Esteller, Luciano Di Croce, Yvan De Launoit, François Fuks

Research output: Contribution to journal › Article › peer-review

1617 Scopus citations

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) 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.

Original language	English (US)
Pages (from-to)	871-874
Number of pages	4
Journal	Nature
Volume	439
Issue number	7078
DOIs	https://doi.org/10.1038/nature04431
State	Published - Feb 16 2006
Externally published	Yes

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The Polycomb group protein EZH2 directly controls DNA methylation. / Viré, Emmanuelle; Brenner, Carmen; Deplus, Rachel; Blanchon, Loïc; Fraga, Mario; Didelot, Céline; Morey, Lluis; Van Eynde, Aleyde; Bernard, David; Vanderwinden, Jean Marie; Bollen, Mathieu; Esteller, Manel; Di Croce, Luciano; De Launoit, Yvan; Fuks, François.

In: Nature, Vol. 439, No. 7078, 16.02.2006, p. 871-874.

Research output: Contribution to journal › Article › peer-review

Viré, Emmanuelle ; Brenner, Carmen ; Deplus, Rachel ; Blanchon, Loïc ; Fraga, Mario ; Didelot, Céline ; Morey, Lluis ; Van Eynde, Aleyde ; Bernard, David ; Vanderwinden, Jean Marie ; Bollen, Mathieu ; Esteller, Manel ; Di Croce, Luciano ; De Launoit, Yvan ; Fuks, François. / The Polycomb group protein EZH2 directly controls DNA methylation. In: Nature. 2006 ; Vol. 439, No. 7078. pp. 871-874.

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title = "The Polycomb group protein EZH2 directly controls DNA methylation",

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 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.",

author = "Emmanuelle Vir{\'e} and Carmen Brenner and Rachel Deplus and Lo{\"i}c Blanchon and Mario Fraga and C{\'e}line Didelot and Lluis Morey and {Van Eynde}, Aleyde and David Bernard and Vanderwinden, {Jean Marie} and Mathieu Bollen and Manel Esteller and {Di Croce}, Luciano and {De Launoit}, Yvan and Fran{\c c}ois Fuks",

note = "Funding Information: 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 T{\'e}l{\'e}vie and the F.N.R.S. L.B. was also supported by the “Fondation pour la Recherche M{\'e}dicale”. D.B. was supported by a Marie Curie Fellowship. F.F. is a “Chercheur Qualifi{\'e} du F.N.R.S.”. This work was supported by grants from MEC-Plan Nacional de I{\th}D{\th}I to L.D.C., and from the “F{\'e}d{\'e}ration Belge contre le Cancer”, the F.N.R.S, “FB Assurances”, and “A.R.C. de la Communaut{\'e} Franc¸aise de Belgique” to Y.d.L. and F.F.",

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AU - Viré, Emmanuelle

AU - Brenner, Carmen

AU - Deplus, Rachel

AU - Blanchon, Loïc

AU - Fraga, Mario

AU - Didelot, Céline

AU - Morey, Lluis

AU - Van Eynde, Aleyde

AU - Bernard, David

AU - Vanderwinden, Jean Marie

AU - Bollen, Mathieu

AU - Esteller, Manel

AU - Di Croce, Luciano

AU - De Launoit, Yvan

AU - Fuks, François

N1 - Funding Information: 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 IþDþI 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 Franc¸aise de Belgique” to Y.d.L. and F.F.

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N2 - 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 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.

AB - 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 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.

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The Polycomb group protein EZH2 directly controls DNA methylation

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