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Team Publications
Maintenance of Transcriptional Repression by Polycomb Proteins
Year of publication 2009
Raphael Margueron, Neil Justin, Katsuhito Ohno, Miriam L Sharpe, Jinsook Son, William J Drury,
Philipp Voigt, Stephen R Martin, William R Taylor, Valeria De Marco, Vincenzo Pirrotta, Danny
Reinberg, Steven J Gamblin (2009 Sep 22)
Role of the polycomb protein EED in the propagation of repressive histone
marks.
Nature : 762-7 : DOI : 10.1038/nature08398
Summary
Polycomb group proteins have an essential role in the epigenetic maintenance of repressive
chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2)
depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET
domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED.
Here we show that the carboxy-terminal domain of EED specifically binds to histone tails
carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this
leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED
that prevent it from recognizing repressive trimethyl-lysine marks abolish the activation of
PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt development. These
findings suggest a model for the propagation of the H3K27me3 mark that accounts for the
maintenance of repressive chromatin domains and for the transmission of a histone
modification from mother to daughter cells.
Year of publication 2008
Raphael Margueron, Guohong Li, Kavitha Sarma, Alexandre Blais, Jiri Zavadil, Christopher L
Woodcock, Brian D Dynlacht, Danny Reinberg (2008 Nov 26)
Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms.
Molecular cell : 503-18 : DOI : 10.1016/j.molcel.2008.11.004
Summary
Polycomb group proteins are critical to maintaining gene repression established during
Drosophila development. Part of this group forms the PRC2 complex containing Ez that
catalyzes di- and trimethylation of histone H3 lysine 27 (H3K37me2/3), marks repressive to
transcription. We report that the mammalian homologs Ezh1 and Ezh2 form similar PRC2
complexes but exhibit contrasting repressive roles. While PRC2-Ezh2 catalyzes H3K27me2/3
and its knockdown affects global H3K27me2/3 levels, PRC2-Ezh1 performs this function
weakly. In accordance, Ezh1 knockdown was ineffectual on global H3K27me2/3 levels.
Instead, PRC2-Ezh1 directly and robustly represses transcription from chromatinized
templates and compacts chromatin in the absence of the methyltransferase cofactor SAM, as
evidenced by electron microscopy. Ezh1 targets a subset of Ezh2 genes, yet Ezh1 is more
abundant in nonproliferative adult organs while Ezh2 expression is tightly associated with
proliferation, as evidenced when analyzing aging mouse kidney. These results might reflect
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Team Publications
Maintenance of Transcriptional Repression by Polycomb Proteins
subfunctionalization of a PcG protein during evolution.
Kavitha Sarma, Raphael Margueron, Alexey Ivanov, Vincenzo Pirrotta, Danny Reinberg (2008 Feb
21)
Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo.
Molecular and cellular biology : 2718-31 : DOI : 10.1128/MCB.02017-07
Summary
The mammalian Polycomblike protein PHF1 was previously shown to interact with the
Polycomb group (PcG) protein Ezh2, a histone methyltransferase whose activity is pivotal in
sustaining gene repression during development and in adulthood. As Ezh2 is active only
when part of the Polycomb Repressive Complexes (PRC2-PRC4), we examined the functional
role of its interaction with PHF1. Chromatin immunoprecipitation experiments revealed that
PHF1 resides along with Ezh2 at Ezh2-regulated genes such as the HoxA loci and the nonHox MYT1 and WNT1 genes. Knockdown of PHF1 or of Ezh2 led to up-regulated HoxA gene
expression. Interestingly, depletion of PHF1 did correlate with reduced occupancy of Bmi-1, a
PRC1 component. As expected, knockdown of Ezh2 led to reduced levels of its catalytic
products H3K27me2/H3K27me3. However, reduced levels of PHF1 also led to decreased
global levels of H3K27me3. Notably, the levels of H3K27me3 decreased while those of
H3K27me2 increased at the up-regulated HoxA loci tested. Consistent with this, the addition
of PHF1 specifically stimulated the ability of Ezh2 to catalyze H3K27me3 but not
H3K27me1/H3K27me2 in vitro. We conclude that PHF1 modulates the activity of Ezh2 in
favor of the repressive H3K27me3 mark. Thus, we propose that PHF1 is a determinant in
PcG-mediated gene repression.
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