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Mechanisms of DNA methylation in mammals
FRANÇOIS FUKS
Free University of Brussels, Faculty of Medicine, 808 route de Lennik, 1070 Brussels,
Belgium.
In mammals, DNA methylation plays an important role in development and is associated with
transcriptional silencing. The goal of our current work is to elucidate the mechanisms by
which the DNA methylation machinery - the DNA methyltransferases (DNMTs) and the
MBDs- functions. In particular, we wish to address two questions: 1. How do the DNMTs and
the MBDs lead to gene silencing? 2. How is the DNMT enzymatic activity regulated?
1. One mechanism by which the DNA methylation machinery brings about transcriptional
repression is through recruitment of HDAC and histone H3 Lys9 methyltransferase activities
(1, 2). Our recent work indicates that DNMTs are mechanistically linked to the Polycomb
Group (PcG) proteins (3). We find that the PcG protein EZH2 interacts with DNA
methyltransferases and associates with DNA methyltransferase activity in vivo. ChIPs
indicate that binding of DNMTs to several EZH2-repressed genes depends on the presence of
EZH2. Furthermore, we show that EZH2 is required for DNA methylation of EZH2-target
promoters. Our results suggest that EZH2 serves as a recruitment platform for DNA
methyltransferases. They highlight a previously unrecognized direct connection between two
fundamental epigenetic repression systems.
2. A key question still poorly understood is how are the DNMTs, and in particular their
enzymatic activity, regulated. Data will be presented that suggest a new mechanism for the
regulation of DNA methylation by post-translational modification.
References
1. Fuks F. Curr Opin Genet Dev. 2005 Oct;15(5):490-5.
2. Brenner C, Deplus R, Didelot C, Loriot A, Vire E, De Smet C, Gutierrez A, Danovi D,
Bernard D, Boon T, Pelicci PG, Amati B, Kouzarides T, de Launoit Y, Di Croce L, Fuks F.
(2005). EMBO J. 24:336-46.
3. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A,
Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F.
Nature. 2005 Dec 14 [Epub ahead of print].
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