Polycomb group proteins are responsible for the heritable repression of genes during development (Lee et al. 2006, Ku et al. 2008, reviewed in Simon and Kingston 2009, Margueron and Reinberg 2011, Di Croce and Helin 2013). Two major families of Polycomb complexes exist: Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). PRC1 and PRC2 each appear to comprise sets of distinct complexes that contain common core subunits and distinct accessory subunits (reviewed in Nayak et al. 2011). PRC2, through its component EZH2 or, in some complexes, EZH1 produces the initial molecular mark of repression, the trimethylation of lysine-27 of histone H3 (H3K27me3). How PRC2 is initially recruited to a locus remains unknown, however cytosine-guanine (CpG) motifs and transcripts have been suggested. Different mechanisms may be used at different loci. The trimethylated H3K27 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.
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Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL.; ''Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.''; PubMedEurope PMCScholia
Xu C, Bian C, Yang W, Galka M, Ouyang H, Chen C, Qiu W, Liu H, Jones AE, MacKenzie F, Pan P, Li SS, Wang H, Min J.; ''Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2).''; PubMedEurope PMCScholia
Swalm BM, Hallenbeck KK, Majer CR, Jin L, Scott MP, Moyer MP, Copeland RA, Wigle TJ.; ''Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys²⁷ methylation by human polycomb repressive complex 2 and vSET.''; PubMedEurope PMCScholia
Simon JA, Kingston RE.; ''Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put.''; PubMedEurope PMCScholia
Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F.; ''The Polycomb group protein EZH2 directly controls DNA methylation.''; PubMedEurope PMCScholia
Kuzmichev A, Jenuwein T, Tempst P, Reinberg D.; ''Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3.''; PubMedEurope PMCScholia
Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, Presser A, Nusbaum C, Xie X, Chi AS, Adli M, Kasif S, Ptaszek LM, Cowan CA, Lander ES, Koseki H, Bernstein BE.; ''Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains.''; PubMedEurope PMCScholia
Chou DM, Adamson B, Dephoure NE, Tan X, Nottke AC, Hurov KE, Gygi SP, Colaiácovo MP, Elledge SJ.; ''A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage.''; PubMedEurope PMCScholia
Simon JA, Kingston RE.; ''Mechanisms of polycomb gene silencing: knowns and unknowns.''; PubMedEurope PMCScholia
Ciferri C, Lander GC, Maiolica A, Herzog F, Aebersold R, Nogales E.; ''Molecular architecture of human polycomb repressive complex 2.''; PubMedEurope PMCScholia
McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, Smitheman KN, Ott HM, Pappalardi MB, Allen KE, Chen SB, Della Pietra A, Dul E, Hughes AM, Gilbert SA, Thrall SH, Tummino PJ, Kruger RG, Brandt M, Schwartz B, Creasy CL.; ''Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27).''; PubMedEurope PMCScholia
Martin C, Cao R, Zhang Y.; ''Substrate preferences of the EZH2 histone methyltransferase complex.''; PubMedEurope PMCScholia
Di Croce L, Helin K.; ''Transcriptional regulation by Polycomb group proteins.''; PubMedEurope PMCScholia
Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D.; ''Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms.''; PubMedEurope PMCScholia
Margueron R, Reinberg D.; ''The Polycomb complex PRC2 and its mark in life.''; PubMedEurope PMCScholia
Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT.; ''Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome.''; PubMedEurope PMCScholia
Li G, Margueron R, Ku M, Chambon P, Bernstein BE, Reinberg D.; ''Jarid2 and PRC2, partners in regulating gene expression.''; PubMedEurope PMCScholia
Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.''; PubMedEurope PMCScholia
Nayak V, Xu C, Min J.; ''Composition, recruitment and regulation of the PRC2 complex.''; PubMedEurope PMCScholia
Neri F, Krepelova A, Incarnato D, Maldotti M, Parlato C, Galvagni F, Matarese F, Stunnenberg HG, Oliviero S.; ''Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs.''; PubMedEurope PMCScholia
Pasini D, Cloos PA, Walfridsson J, Olsson L, Bukowski JP, Johansen JV, Bak M, Tommerup N, Rappsilber J, Helin K.; ''JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells.''; PubMedEurope PMCScholia
Hagarman JA, Motley MP, Kristjansdottir K, Soloway PD.; ''Coordinate regulation of DNA methylation and H3K27me3 in mouse embryonic stem cells.''; PubMedEurope PMCScholia
Brinkman AB, Gu H, Bartels SJ, Zhang Y, Matarese F, Simmer F, Marks H, Bock C, Gnirke A, Meissner A, Stunnenberg HG.; ''Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk.''; PubMedEurope PMCScholia
Mendenhall EM, Koche RP, Truong T, Zhou VW, Issac B, Chi AS, Ku M, Bernstein BE.; ''GC-rich sequence elements recruit PRC2 in mammalian ES cells.''; PubMedEurope PMCScholia
Smits AH, Jansen PW, Poser I, Hyman AA, Vermeulen M.; ''Stoichiometry of chromatin-associated protein complexes revealed by label-free quantitative mass spectrometry-based proteomics.''; PubMedEurope PMCScholia
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y.; ''Role of histone H3 lysine 27 methylation in Polycomb-group silencing.''; PubMedEurope PMCScholia
The Polycomb Repressor Complex 2 (PRC2) is able to interact with and recruit DNMT1, DNMT3a, and DNMT3b, all of which transfer a methyl group from S-adenosylmethionine to the 5 position of the cytosine ring.EZH2 is required for DNA methylation at PRC2 targets.
The Polycomb Repressor Complex 2 (PRC2) is able to interact with and recruit DNMT1, DNMT3a, and DNMT3b, all of which transfer a methyl group from S-adenosylmethionine to the 5 position of the cytosine ring.EZH2 is required for DNA methylation at PRC2 targets.
In tumor cells the Polycomb Repressor Complex 2 associates with a DNA methyltransferase (DNMT) via the N-terminal region of EZH2 (Vire et al. 2006). DNMT1, DNMT3a, and DNMT3b can each bind EZH2 though only one is bound at any time. As inferred from mouse (Rush et al. 2009), EZH2 tethered to a locus is able to recruit Dnmt3a but additional factors may be required to trigger de novo DNA methylation. It is unknown if the DNMT is recruited only after PRC2 has been targeted to a locus.
The core of the Polycomb Repressor Complex 2 (PRC2) contains EZH2, EED, SUV12, RpAp46, and RpAp48 (Kuzzmichev et al. 2002, Cao et al. 2002). PRC2 complexes at different sites in the genome contain the core subunits plus different accessory subunits. In Drosophila PRC2 is recruited to chromatin by specific DNA sequences. In vertebrates PRC2 appears to be recruited to chromatin through several mechanisms: some (about 20%) of noncoding RNAs tethered to the locus of origin recruit PRC2 via the RNA-binding activity of EZH2 (Zhao et al. 2008, Khalil et al. 2009), GC-rich sequence elements in DNA (Mendenhall et al. 2010) and poly(ADP-ribosyl) polymerase at sites of DNA damage (Chou et al. 2010) can also recruit polycomb components, The DNA-binding proteins JARID2, AEBP2, and YY1 recruit PRC2 (Pasini et al. 2010, Li et al. 2010, reviewed in Kim and Kim 2012). The EED subunit of PRC2 can bind existing trimethylated lysine-27 on histone H3 of PRC2 which may provide a mechanism for propagation of trimethylated lysine-27 during DNA replication (Xu et al. 2010).
EZH2 , a SET domain protein, trimethylates histone H3 at lysine 27 (H3K27) and lysine 9 (H3K9) (Kuzmichev et al. 2002, Cao et al. 2002, Kuzmichev et al. 2004, Martin et al. 2006, McCabe et al. 2012, Swalm et al. 2013). EZH2 has greater activity with lysine residues that have fewer methyl groups (unmethylated:monomethylated:dimethylated=9:6:1, McCabe et al. 2012). EZH1 rather than EZH2 is present in some PRC2 complexes and can also catalyze the trimethylation of H3K27 (inferred from mouse in Shen et al. 2008), however EZH1 is also able to repress transcription without methylating histone H3 (Margueron et al. 2008).
DNA methyltransferases (DNMTs) associate with EZH2 of the Polycomb Repressive Complex 2 (PRC2) and methylate the 5 position of the cytosine ring in DNA (Vire et al. 2006). The histone methyltransferase activity of EZH2 also trimethylates lysine-27 of histone H3 (H3K27me3). The promoters of the MYT, WNT1, KCNA1, and CNR1 genes are methylated on cytosine by the DNMT:PRC2 complex however not all loci that have H3K27me3 by PRC2 also have cytosine methylation (Vire et al. 2006, Brinkman et al. 2012). DNA methylation and H3K27me3 appear to be mutually exclusive in CpG islands but are compatible throughout most of the rest of the genome (Brinkman et al. 2012). In mouse, DNA methylation and H3K27me3 appear to be antagonistic at most loci: loss of DNA methylation causes increased H3K27me3 while loss of PRC2 has little effect on DNA methylation (Hagarman et al. 2013). By competing with DNMT3a,b for association with PRC2, DNMT3L may antagonize DNA methylation at sites bound by PRC2 (Neri et al. 2013).
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