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Molecular and Cellular Biology, March 2007, p. 2014-2026, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01822-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The N Terminus of Drosophila ESC Binds Directly to Histone H3 and Is Required for E(Z)-Dependent Trimethylation of H3 Lysine 27{triangledown}

Feng Tie,* Carl A. Stratton, Rebeccah L. Kurzhals, and Peter J. Harte*

Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106

Received 26 September 2006/ Returned for modification 7 November 2006/ Accepted 19 December 2006

Polycomb group proteins mediate heritable transcriptional silencing and function through multiprotein complexes that methylate and ubiquitinate histones. The 600-kDa E(Z)/ESC complex, also known as Polycomb repressive complex 2 (PRC2), specifically methylates histone H3 lysine 27 (H3 K27) through the intrinsic histone methyltransferase (HMTase) activity of the E(Z) SET domain. By itself, E(Z) exhibits no detectable HMTase activity and requires ESC for methylation of H3 K27. The molecular basis for this requirement is unknown. ESC binds directly, via its C-terminal WD repeats (ß-propeller domain), to E(Z). Here, we show that the N-terminal region of ESC that precedes its ß-propeller domain interacts directly with histone H3, thereby physically linking E(Z) to its substrate. We show that when expressed in stable S2 cell lines, an N-terminally truncated ESC (FLAG-ESC61-425), like full-length ESC, is incorporated into complexes with E(Z) and binds to a Ubx Polycomb response element in a chromatin immunoprecipitation assay. However, incorporation of this N-terminally truncated ESC into E(Z) complexes prevents trimethylation of histone H3 by E(Z). We also show that a closely related Drosophila melanogaster paralog of ESC, ESC-like (ESCL), and the mammalian homolog of ESC, EED, also interact with histone H3 via their N termini, indicating that the interaction of ESC with histone H3 is evolutionarily conserved, reflecting its functional importance. Our data suggest that one of the roles of ESC (and ESCL and EED) in PRC2 complexes is to enable E(Z) to utilize histone H3 as a substrate by physically linking enzyme and substrate.

* Corresponding author. Mailing address: Department of Genetics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4955. Phone: (216) 368-6417. Fax: (216) 368-3432. E-mail for Peter J. Harte: pjh3{at}po.cwru.edu. E-mail for Feng Tie: fxt8{at}case.edu.

{triangledown} Published ahead of print on 8 January 2007.

Molecular and Cellular Biology, March 2007, p. 2014-2026, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01822-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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