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Molecular and Cellular Biology, April 2008, p. 2718-2731, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.02017-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Ezh2 Requires PHF1 To Efficiently Catalyze H3 Lysine 27 Trimethylation In Vivo{triangledown}

Kavitha Sarma,3 Raphael Margueron,2 Alexey Ivanov,5 Vincenzo Pirrotta,4 and Danny Reinberg1,2,3*

Howard Hughes Medical Institute,1 Department of Biochemistry, NYU Medical School, 522 First Ave., New York, New York 10016,2 Department of Biochemistry, Division of Nucleic Acids Enzymology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, New Jersey 08854,3 Department of Molecular Biology and Biochemistry, Rutgers University, Nelson Laboratories, 604 Allison Road, Piscataway, New Jersey 08854,4 The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 191045

Received 9 November 2007/ Returned for modification 6 December 2007/ Accepted 5 February 2008

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.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, NYU School of Medicine-Smilow Research Center, Biochemistry Department, 522 First Avenue, 2nd Floor, Room 211, New York, NY 10016. Phone: (212) 263-9036. Fax: (212) 263-9040. E-mail: reinbd01{at}med.nyu.edu

{triangledown} Published ahead of print on 19 February 2008.

Molecular and Cellular Biology, April 2008, p. 2718-2731, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.02017-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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