XB-ART-57835
Nat Commun
January 1, 2021;
12
(1):
714.
Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction.
Grau D
,
Zhang Y
,
Lee CH
,
Valencia-Sánchez M
,
Zhang J
,
Wang M
,
Holder M
,
Svetlov V
,
Tan D
,
Nudler E
,
Reinberg D
,
Walz T
,
Armache KJ
.
Abstract
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase critical for maintaining gene silencing during eukaryotic development. In mammals, PRC2 activity is regulated in part by the selective incorporation of one of two paralogs of the catalytic subunit, EZH1 or EZH2. Each of these enzymes has specialized biological functions that may be partially explained by differences in the multivalent interactions they mediate with chromatin. Here, we present two cryo-EM structures of PRC2:EZH1, one as a monomer and a second one as a dimer bound to a nucleosome. When bound to nucleosome substrate, the PRC2:EZH1 dimer undergoes a dramatic conformational change. We demonstrate that mutation of a divergent EZH1/2 loop abrogates the nucleosome-binding and methyltransferase activities of PRC2:EZH1. Finally, we show that PRC2:EZH1 dimers are more effective than monomers at promoting chromatin compaction, and the divergent EZH1/2 loop is essential for this function, thereby tying together the methyltransferase, nucleosome-binding, and chromatin-compaction activities of PRC2:EZH1. We speculate that the conformational flexibility and the ability to dimerize enable PRC2 to act on the varied chromatin substrates it encounters in the cell.
PubMed ID: 33514705
Article link: Nat Commun
Grant support: [+]
R01 CA199652 NCI NIH HHS , T32 HL007151 NHLBI NIH HHS , P41 GM103310 NIGMS NIH HHS , Howard Hughes Medical Institute , U24 GM129547 NIGMS NIH HHS , R01 GM115882 NIGMS NIH HHS , P30 CA016087 NCI NIH HHS , R01 GM126891 NIGMS NIH HHS
Species referenced: Xenopus laevis
Genes referenced: aebp2 eed ezh1 jarid2 rbbp4 suz12
Article Images: [+] show captions
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Cao, SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. 2004, Pubmed
Cao, Role of histone H3 lysine 27 methylation in Polycomb-group silencing. 2002, Pubmed
Chen, Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding. 2019, Pubmed
Chen, A Dimeric Structural Scaffold for PRC2-PCL Targeting to CpG Island Chromatin. 2020, Pubmed
Ciferri, Molecular architecture of human polycomb repressive complex 2. 2015, Pubmed
Cooper, Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2. 2018, Pubmed
Davidovich, A dimeric state for PRC2. 2014, Pubmed
Diehl, PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor. 2020, Pubmed
Dyer, Reconstitution of nucleosome core particles from recombinant histones and DNA. 2004, Pubmed
Emsley, Features and development of Coot. 2010, Pubmed
Ezhkova, EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. 2011, Pubmed
Gibson, Organization of Chromatin by Intrinsic and Regulated Phase Separation. 2020, Pubmed
Grau, Compaction of chromatin by diverse Polycomb group proteins requires localized regions of high charge. 2011, Pubmed
Grossniklaus, Transcriptional silencing by polycomb-group proteins. 2015, Pubmed
Hansen, A model for transmission of the H3K27me3 epigenetic mark. 2008, Pubmed
Hidalgo, Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. 2013, Pubmed
Højfeldt, Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2. 2019, Pubmed
Justin, Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. 2018, Pubmed
Kalb, Histone H2A monoubiquitination promotes histone H3 methylation in Polycomb repression. 2014, Pubmed
Kasinath, Structures of human PRC2 with its cofactors AEBP2 and JARID2. 2018, Pubmed
Kastner, GraFix: sample preparation for single-particle electron cryomicroscopy. 2008, Pubmed
Kimanius, Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2. 2017, Pubmed
Kuzmichev, Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. 2002, Pubmed
Laible, Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. 1997, Pubmed
Larson, Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. 2017, Pubmed
Lau, Mutation of a nucleosome compaction region disrupts Polycomb-mediated axial patterning. 2017, Pubmed
Laugesen, Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation. 2019, Pubmed
Lee, Allosteric Activation Dictates PRC2 Activity Independent of Its Recruitment to Chromatin. 2019, Pubmed
Lee, Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2. 2019, Pubmed
Lee, Assembly of nucleosomal templates by salt dialysis. 2008, Pubmed
Lejon, Insights into association of the NuRD complex with FOG-1 from the crystal structure of an RbAp48·FOG-1 complex. 2011, Pubmed
Lewis, Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. 2013, Pubmed
Lewis, A gene complex controlling segmentation in Drosophila. 1979, Pubmed
Li, Jarid2 and PRC2, partners in regulating gene expression. 2010, Pubmed
Margueron, Role of the polycomb protein EED in the propagation of repressive histone marks. 2009, Pubmed
Margueron, Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. 2009, Pubmed
Mastronarde, Automated electron microscope tomography using robust prediction of specimen movements. 2005, Pubmed
Millard, The structure of the core NuRD repression complex provides insights into its interaction with chromatin. 2016, Pubmed
Müller, Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. 2002, Pubmed
Ohi, Negative Staining and Image Classification - Powerful Tools in Modern Electron Microscopy. 2020, Pubmed
Oksuz, Capturing the Onset of PRC2-Mediated Repressive Domain Formation. 2019, Pubmed
Pettersen, UCSF Chimera--a visualization system for exploratory research and analysis. 2004, Pubmed
Pettersen, UCSF ChimeraX: Structure visualization for researchers, educators, and developers. 2020, Pubmed
Plys, Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2. 2019, Pubmed
Poepsel, Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes. 2019, Pubmed
Punjani, cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. 2017, Pubmed
Rohou, CTFFIND4: Fast and accurate defocus estimation from electron micrographs. 2016, Pubmed
Rueden, ImageJ2: ImageJ for the next generation of scientific image data. 2018, Pubmed
Schmitges, Histone methylation by PRC2 is inhibited by active chromatin marks. 2011, Pubmed
Shen, EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. 2009, Pubmed
Sigler, Transcriptional activation. Acid blobs and negative noodles. 1988, Pubmed
Son, Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin. 2014, Pubmed
Stafford, Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma. 2019, Pubmed
Strom, Phase separation drives heterochromatin domain formation. 2017, Pubmed
Tatavosian, Nuclear condensates of the Polycomb protein chromobox 2 (CBX2) assemble through phase separation. 2019, Pubmed
Valencia-Sánchez, Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination. 2019, Pubmed
Vo, Regulation of embryonic haematopoietic multipotency by EZH1. 2018, Pubmed
Waterhouse, SWISS-MODEL: homology modelling of protein structures and complexes. 2019, Pubmed
Weissmann, biGBac enables rapid gene assembly for the expression of large multisubunit protein complexes. 2016, Pubmed
Yu, PRC2 is high maintenance. 2019, Pubmed
Zheng, MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. 2019, Pubmed
Zivanov, New tools for automated high-resolution cryo-EM structure determination in RELION-3. 2019, Pubmed