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Phf19 Links Methylated Lys36 of Histone H3 to Regulation of Polycomb Activity

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Phf19 Links Methylated Lys36 of Histone H3 to Regulation of Polycomb Activity ARTICLES Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity Cecilia Ballaré1,2,8, Martin Lange1,2,8, Audrone Lapinaite3,8, Gloria Mas Martin4, Lluis Morey1,2, Gloria Pascual1,2, Robert Liefke5,6, Bernd Simon3, Yang Shi5,6, Or Gozani4, Teresa Carlomagno3, Salvador Aznar Benitah1,2,7 & Luciano Di Croce1,2,7 Polycomb-group proteins are transcriptional repressors with essential roles in embryonic development. Polycomb repressive complex 2 (PRC2) contains the methyltransferase activity for Lys27. However, the role of other histone modifications in regulating PRC2 activity is just beginning to be understood. Here we show that direct recognition of methylated histone H3 Lys36 (H3K36me), a mark associated with activation, by the PRC2 subunit Phf19 is required for the full enzymatic activity of the PRC2 complex. Using NMR spectroscopy, we provide structural evidence for this interaction. Furthermore, we show that Phf19 binds to a subset of PRC2 targets in mouse embryonic stem cells and that this is required for their repression and for H3K27me3 deposition. These findings show that the interaction of Phf19 with H3K36me2 and H3K36me3 is essential for PRC2 complex activity and for proper regulation of gene repression in embryonic stem cells. Polycomb group proteins have important roles in regulating embry- and Phf19) contain several domains that have been implicated in onic development1,2 and have been implicated in embryonic stem recognizing methylated histone residues. cell pluripotency3–7. The two Polycomb complexes, PRC1 and PRC2, In this study, we have investigated the role of Phf19 in regulating have been characterized in depth. The PRC2 complex trimethylates PRC2 activity in mES cells. We report that Phf19 is associated with histone H3 Lys27 (H3K27me3)8, providing a docking site for pro- PRC2 proteins in a complex lacking Jarid2. Biophysical and struc- teins with a chromobox (Cbx) domain9. Proteins in the Cbx family tural data show that the Tudor domain of Phf19 binds with high are subunits of the PRC1 complex, and they facilitate PRC1 recruit- affinity to methylated H3K36, a characteristic shared by all members ment to target genes. The two complexes can silence genes either of the PCL family. Depletion of Phf19 caused a global reduction of © 2012 Nature America, Inc. All rights reserved. America, Inc. © 2012 Nature synergistically or independently of each other. Thus, regulation of H3K27me3 and impaired the occupancy of PRC2 complex genome- H3K27 methylation represents an essential step in gene regulation wide. We observed similar effects in cells ectopically expressing by Polycomb proteins. In flies, the Polycomb complexes are recruited Phf19 carrying a point mutation in its Tudor domain. Phf19 knock- npg to chromatin at the Polycomb responsive elements (PRE). Although down ES cells showed loss of pluripotency and defects in differentia- a few mammalian PRE sequences have been identified10,11, it is still tion. Mechanistically, we further show that Phf19 has a pivotal role unclear how Polycomb group proteins are recruited to genome in silencing active promoters by directly targeting the PRC2 complex loci. Recent data suggest that mammalian PRC2 preferentially binds and H3K36 histone demethylases. Our data indicate that Phf19 is an to CpG islands12. Moreover, long noncoding RNAs and transcrip- important regulator of PRC2 function in mES cells. tion factors have also been implicated in modulating Polycomb group protein occupancy13. Among those, Jarid2 has been impli- RESULTS cated in regulating the binding of the PRC2 complex to genomic Phf19 is a component of the PRC2 complex targets in mouse embryonic stem (mES) cells; however, there are We initially purified proteins that associate with Phf19, one of likely to be other mechanisms for fine-tuning14–17. For example, in the Pcl orthologs in vertebrates, from 293T cells using tandem- Drosophila melanogaster, the Polycomb-like protein (Pcl) associates affinity immunopurification (TAP) followed by SDS-PAGE and with PRC2 and is required for global H3K27 trimethylation18,19. silver staining (Fig. 1a). MS analysis and western blotting of the A role for Polycomb-like proteins in regulating H3K27 trimeth- TAP purification showed that PHF19 associates with core sub- ylation seems to be conserved in higher vertebrates20–23. Notably, units EZH2, SUZ12 and EED of PRC2 (Fig. 1b,c). Moreover, we all members of the human PCL family of proteins (Phf1, MTF2 identified the proteins RBBP4 and RBBP7, which are also part of 1Department of Gene Regulation and Stem Cells, Centre for Genomic Regulation (CRG), Barcelona, Spain. 2Universitat Pompeu Fabra, Barcelona, Spain. 3Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. 4Department of Biological Sciences, Stanford University, Stanford, California, USA. 5Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 6Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 7Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. 8These authors contributed equally to this work. Correspondence should be addressed to L.D.C. ([email protected]). Received 18 April; accepted 3 October; published online 28 October 2012; doi:10.1038/nsmb.2434 NATURE STRUCTURAL & MOLECULAR BIOLOGY VOLUME 19 NUMBER 12 DECEMBER 2012 1257 ARTICLES Figure 1 Phf19 is a component of the PRC2 a TAP- b c TAP Input eluates complex. (a) SDS-PAGE followed by silver M TAP– PHF19 kDa Mass staining of TAP-purified PHF19 (TAP-PHF19) 260 160 Protein(kDa) Score Peptides emPAI in 293T cells. TAP−, TAP-empty. (b) Summary 110 SUZ12 80 EZH2 PHF19 67.531 327 12 0.8 TAP– PHF19 TAP– TAP– PHF19 TAP– of peptides identified by MS in eluates from PHF19 SUZ12 83.003 917 28 1.5 60 EZH2 TAP-PHF19 purification. emPAI, experimentally EED EZH2 80.986 271 9 0.31 RBBP4 and PHF19-CBP 50 EED 45.495 115 5 0.37 modified protein abundance. (c) Western blot RBBP7 40 RBBP7 47.79 273 7 0.57 SUZ12 analysis of eluates from TAP-PHF19 purification RBBP4 47.626 205 7 0.57 30 EED confirming the specific association with the 20 RING1B PRC2. Note that the PRC1 subunit RING1b 15 does not interacts with PHF19. (d) Endogenous 1.43 mDa 792 kDa co-immunoprecipitation (IP) in mES cells of d e Phf19 with PRC2 components. Note that Jarid2 Fraction InputVoid 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 Input IP Phf19IgGs EZH2 is not present in Phf19–PRC2 complexes. Ezh2 SUZ12 (e) Size-exclusion chromatography of 293T Phf19 nuclear extracts followed by western blotting. F-PHF19 Eed Note that PHF19 and JARID2 co-migrate with EED Jarid2 components of the PRC2 complex but elute JARID2 at different size fractions—around 790 kDa and 1.4 mDa, respectively. (f) Schematic f g 10% input IP Flag representation of the domain architecture of TudorPHD1PHD2EH Chromo PHF19 human PHF19, depicting the Tudor domain, 1 580 1–174 two plant homeodomain (PHD) fingers, the 1 174 175–366 kDa extended homology (EH) domain, and a 175 366 Empty 1–174 175–366 367–580 1–499 500–580 PHF19S Empty 1–174 175–366 367–580 1–499 500–580 PHF19S 367–580 100 chromo-like domain. (g) The chromo-like 367 580 75 SUZ12 1–499 domain is necessary and sufficient to 1 499 50 Heavy chain 500–580 co-immunoprecipitate the endogenous PRC2 Tail 500 580 37 PHF19S 25 Light chain core component SUZ12. (h) Predicted secondary 1 207 HA structures of the chromo-like domains compared to the first chromodomain of the HP1 proteins. α-helix β-sheet β-sheet α-helix h PHF19 527 580 MTF2 540 593 PHF1 513 567 PCL 981 1043 chromodomain’. Notably, the α-helix seems CBX1(HP1-β) 13 79 CBX3(HP1-γ) 22 88 to be conserved among Mtf2, Phf19 and the CBX5(HP1-α) 12 78 D. melanogaster homolog Pcl, but it was not ****** predicted for Phf1. PRC2 (Fig. 1b,c). We confirmed the interaction of PHF19 Phf19’s Tudor domain binds to di- and trimethylated H3K36 with endogenous components of the PRC2 complex using To determine the domains necessary for regulating PRC2 activity at chro- co-immunoprecipitation (co-IP) experiments in mES cells matin, we tested the purified, recombinantly expressed Phf19 domains © 2012 Nature America, Inc. All rights reserved. America, Inc. © 2012 Nature (Fig. 1d). Size-exclusion chromatography24 followed by western for binding to a histone peptide array27 (Fig. 2a). The Tudor domain of blotting showed that the majority of Phf19 co-migrates with Phf19 bound to dimethylated (me2) and trimethylated (me3) H3K36, but the PRC2 (Fig. 1e), indicating that Phf19 is stably associated not to numerous other methylated peptides. Histone peptide pull-down npg with this Polycomb complex. Notably, Jarid2, a protein recently assays confirmed the specificity of the interaction (Fig. 2b). identified as a PRC2 subunit, did not co-immunoprecipitate We next asked whether the H3K36 interaction is conserved among with Phf19, and the corresponding elution profile of Jarid2 peaked proteins of this family, including the mammalian homologs Phf1 (Pcl1) at a different fraction by size-exclusion chromatography. This and Mtf2 (Pcl2) and D. melanogaster Pcl. We found that the Tudor- suggests that Jarid2 and Phf19 reside in different PRC2 subcom- H3K36 interaction is conserved among all proteins of the family, but plexes. Of note, none of the previous Jarid2 purifications has D. melanogaster Pcl did not bind H3K36me2 or H3K36me3. Sequence identified Phf19 as a subunit of PRC2 (refs. 14–17). comparison of the Tudor domain among the Pcl family members Polycomb-like proteins are evolutionarily conserved from flies showed that several amino acids are conserved, including a set of aro- to humans, and they contain a Tudor domain, two adjacent plant- matic residues (Supplementary Fig.
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