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Mol Cell Biol. 2008 Apr;28(8):2718-31. doi: 10.1128/MCB.02017-07. Epub 2008 Feb 19.

Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo.

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  • 1Howard Hughes Medical Institute, NYU School of Medicine-Smilow Research Center, Biochemistry Department, 522 First Avenue, 2nd Floor, Room 211, New York, NY 10016, USA.

Abstract

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 non-Hox 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.

PMID:
18285464
[PubMed - indexed for MEDLINE]
PMCID:
PMC2293112
Free PMC Article

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