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Binding of Different Histone Marks Differentially Regulates the Activity and Specificity of Polycomb Repressive Complex 2 (PRC2)

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Binding of Different Histone Marks Differentially Regulates the Activity and Specificity of Polycomb Repressive Complex 2 (PRC2) Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2) Chao Xua,1, Chuanbing Biana,1, Wei Yangb,1, Marek Galkac, Hui Ouyanga, Chen Chend, Wei Qiua, Huadong Liuc, Amanda E. Jonesb, Farrell MacKenziea, Patricia Pana,e, Shawn Shun-Cheng Lic,2, Hengbin Wangb,2, and Jinrong Mina,f,2 aStructural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON, Canada M5G 1L7; bDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Kaul Human Genetics Building Room 430, 720 South 20th Street South, Birmingham, AL 35294; cDepartment of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 5C1; dSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5; eDepartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9; and fDepartment of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8 Edited by Tony Pawson, Samuel Lunenfeld Research Institute, Toronto, Canada, and approved September 14, 2010 (received for review June 23, 2010) The polycomb repressive complex 2 (PRC2) is the major methyltrans- tional silencing through an unknown mechanism (11). In addition ferase for H3K27 methylation, a modification critical for maintain- to silencing Hox genes, the polycomb group complexes are also ing repressed gene expression programs throughout development. involved in X-inactivation, germ-line development, stem cell It has been previously shown that PRC2 maintains histone methyl- pluripotency and differentiation, and cancer metastasis (2). ation patterns during DNA replication in part through its ability to PRC2 complex contains four core components: EZH2, EED, bind to H3K27me3. However, the mechanism by which PRC2 recog- SUZ12, and RbAp46/48. The catalytic activity of PRC2 is con- nizes H3K27me3 is unclear. Here we show that the WD40 domain of ferred by the suppressor of variegation [Su(var)3-9], enhancer EED, a PRC2 component, is a methyllysine histone-binding domain. of zeste [E(z)], and trithorax (SET) domain in EZH2, but PRC2 The crystal structures of apo-EED and EED in complex respectively exhibits robust methylation activity only as a complex because in with five different trimethyllysine histone peptides reveal that EED vitro enzymatic assays indicate that EZH2 has virtually no histone binds these peptides via the top face of its β-propeller architecture. methylation activity on its own (6). Biochemical and genetic The ammonium group of the trimethyllysine is accommodated by studies suggest that both EED and SUZ12 are required for the an aromatic cage formed by three aromatic residues, while its ali- integrity of PRC2 and PRC2-mediated H3K27 methylation be- phatic chain is flanked by a fourth aromatic residue. Our structural cause mutations in either protein lead to EZH2 to destabilization data provide an explanation for the preferential recognition of the and deficient methylation of H3K27 (12–14). Ala-Arg-Lys-Ser motif-containing trimethylated H3K27, H3K9, and EED contains seven WD40 repeats at its C terminus (residues H1K26 marks by EED over lower methylation states and other his- 81–441) preceded by a small N-terminal domain (residues 1–80). tone methyllysine marks. More importantly, we found that binding Studies of the Drosophila EED orthologue extra sex combs (ESC) of different histone marks by EED differentially regulates the activ- revealed that the N-terminal region interacts directly with the ity and specificity of PRC2. Whereas the H3K27me3 mark stimulates core domain of histone H3 and that this interaction is essential the histone methyltransferase activity of PRC2, the H1K26me3 for E(Z)-dependent trimethylation of H3K27 (15). Furthermore, mark inhibits PRC2 methyltransferase activity on the nucleosome. although an N-terminally truncated ESC can form a complex Moreover, H1K26me3 binding switches the specificity of PRC2 with E(Z) when expressed in stable S2 cell lines, this complex from methylating H3K27 to EED. In addition to determining the cannot carry out trimethylation of histone H3 (15). A similar molecular basis of EED-methyllysine recognition, our work provides mechanism may regulate PRC2 function in vertebrates because the biochemical characterization of how the activity of a histone the ESC/EED–histone H3 interaction is evolutionarily conserved methyltransferase is oppositely regulated by two histone marks. (15). The WD40 repeat is a structural motif of approximately ∣ ∣ methyllysine-binding domain WD40 repeat-containing protein 40 amino acids, which forms a four-stranded antiparallel β-sheet X-ray crystallography and often contains a Gly-His dipeptide at the end of the fourth strand and a Trp-Asp dipeptide at the end of the third strand (16). he polycomb (PcG) and trithorax groups of proteins act in Most WD40 repeat proteins contain seven or eight WD40 repeats Tconcert to maintain the transcriptional state of developmental and adopt a β-propeller architecture. WD40 proteins are involved Hox control genes such as the genes. These patterns are estab- in diverse functions such as transcription regulation, signal trans- lished during early embryonic development and are heritable through many generations of cell division (1–3). Polycomb group proteins are transcriptional repressors that maintain target genes Author contributions: C.X., C.B., W.Y., M.G., S.S.-C.L., H.W., and J.M. designed research; in an inactive state, whereas trithorax group proteins are tran- C.X., C.B., W.Y., M.G., H.O., W.Q., H.L., A.E.J., F.M., and P.P. performed research; C.X., C.B., W.Y., M.G., H.O., C.C., W.Q., H.L., S.S.-C.L., H.W., and J.M. analyzed data; and J.M. scriptional activators that maintain their target genes in an active wrote the paper. state. This system of cellular memory is conserved in nearly all The authors declare no conflict of interest. multicellular eukaryotes (4). This article is a PNAS Direct Submission. PcG proteins often function as complexes, and the two best- characterized complexes are the polycomb repressive complex Freely available online through the PNAS open access option. 1 (PRC1) and 2 (PRC2). PRC2 exhibits histone methyltransferase Data deposition: The crystallography, atomic coordinates, and structure factors have – been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3JZN, 3K26, activity on H3K27 (2, 5 7) and weakly on H1K26 (8). Studies 3K27, 3JZG, 3JZH, and 3JPX). Drosophila in have shown that PRC1 contains a chromodomain 1C.X., C.B., and W.Y. contributed equally to this work. protein, polycomb, which preferentially recognizes the histone 2To whom correspondence may be addressed. E-mail: [email protected], [email protected], or jr. H3K27me3 mark (9, 10). One hypothesis is that H3K27 methyl- [email protected]. ation by PRC2 creates a binding site recognized by the chromo- This article contains supporting information online at www.pnas.org/lookup/suppl/ domain of polycomb of PRC1, which in turn maintains transcrip- doi:10.1073/pnas.1008937107/-/DCSupplemental. 19266–19271 ∣ PNAS ∣ November 9, 2010 ∣ vol. 107 ∣ no. 45 www.pnas.org/cgi/doi/10.1073/pnas.1008937107 Downloaded by guest on September 26, 2021 duction, vesicular trafficking, cytoskeletal assembly, cell cycle selective binding of EED to trimethylated lysine histones by de- control, and apoptosis (16). A common function of these WD40 termining the crystal structure of apo-EED and its complexes repeat proteins is to serve as a scaffold for protein–protein or with five trimethylated histone peptides, respectively. protein–DNA interactions and to coordinate downstream events. Since the first WD40 repeat structure Gβ was solved (17, 18), tens Results and Discussion of WD40 structures have been reported, which, together, show The WD40 Repeat Domain of EED Selectively Recognizes Trimethylated that the WD40 β-propeller is capable of recognizing a diverse Histone Peptides. PRC2 methylates histone lysine residues, mainly group of ligands, including proteins (17, 18), phosphopeptides on H3K27 (2, 5–7), and also binds to the H3K27me3 mark (32). (19–21), and nucleic acids (22), mainly through the small top sur- Efficient binding requires a ternary complex of EZH2, EED, face. For example, WDR5 uses the top surface of its β-propeller and SUZ12 but is independent of the catalytic SET domain of to recognize histone H3K4 peptide (23–26) or a mixed lineage EZH2 (32). However, which component in PRC2 is responsible leukemia (MLL) fragment (27–29). WDR5 recognizes a peptide for binding to H3K27me3 is unclear. Aided by the crystal struc- through an arginine residue that inserts into the central pore ture of EED in complex with a short N-terminal fragment of of the β-propeller and anchors the peptides into a shallow groove EZH2 (30), we identified an aromatic cage on the top face of the at its top face. EED β-propeller structure (Fig. 1A), raising the possibility that WD40 proteins can also bind their ligands through the larger EED may mediate direct binding of PRC2 to H3K27me3 through bottom surface. For example, the structure of the WD40 repeat this aromatic cage. To test this hypothesis, we measured the domain of EED in complex with an N-terminal fragment binding of EED to a panel of peptides that represented the of EZH2 revealed that the peptide bound to the WD40 repeat histone marks H3K4, H3K9, H3K27, H3K36, H3K79, H4K20, domain of EED on the larger bottom surface (Fig. 1A) (30). and H1K26 in different methylation states (Fig. 1 B and C). Mutations in the WD40 region of the ESC perturbed its binding We found that EED preferentially bound trimethylated histone to E(Z) in vitro and abolished its silencing function in vivo (31). peptides, with higher affinities to the H3K9me3, H1K26me3, Recently, it was shown that the EZH2–EED–SUZ12 trimeric and H3K27me3 peptides than the other trimethylated histone PRC2 complex binds to and colocalizes with the H3K27me3 mark peptides.
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