Recent Structural Insights into Polycomb Repressive Complex 2 Regulation and Substrate Binding.

Polycomb group proteins are transcriptional repressors controlling gene expression patterns and maintaining cell type identity. The chemical modifications of histones and DNA caused by the regulated activity of chromatin-modifying enzymes such as Polycomb help establish and maintain such expression patterns. Polycomb repressive complex 2 (PRC2) is the only known methyltransferase specific for histone H3 lysine 27 (H3K27) and catalyzes its trimethylation leading to the repressive H3K27me3 mark. Structural biology has made important contributions to our understanding of the molecular mechanisms that ensure the spatiotemporal regulation of PRC2 activity and the establishment of inactive chromatin domains marked by H3K27me3. In this review, we discuss the recent structural studies that have advanced our understanding of PRC2 function, in particular the roles of intersubunit interactions in complex assembly and the regulation of methyltransferase activity, as well as the mechanism of local H3K27me3 spreading leading to repressive domains.

[1]  T. Cech,et al.  Promiscuous RNA binding by Polycomb Repressive Complex 2 , 2013, Nature Structural &Molecular Biology.

[2]  Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2. , 2018, Molecular cell.

[3]  Hana Kim,et al.  AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2 , 2009 .

[4]  Kristian Helin,et al.  Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. , 2006, Genes & development.

[5]  Pedro P. Rocha,et al.  Capturing the onset of PRC2-mediated repressive domain formation , 2018, bioRxiv.

[6]  Haruhiko Koseki,et al.  Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. , 2004, Developmental cell.

[7]  B. Garcia,et al.  Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma , 2013, Science.

[8]  Darren J. Fitzpatrick,et al.  A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities. , 2018, Molecular cell.

[9]  D. Reinberg,et al.  Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome. , 2014, Molecular cell.

[10]  N. Brockdorff,et al.  Functional analysis of AEBP2, a PRC2 Polycomb protein, reveals a Trithorax phenotype in embryonic development and in ESCs , 2016, Development.

[11]  P. Atadja,et al.  An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. , 2017, Nature chemical biology.

[12]  S. Orkin,et al.  Jumonji Modulates Polycomb Activity and Self-Renewal versus Differentiation of Stem Cells , 2009, Cell.

[13]  Yi Zhang,et al.  SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. , 2004, Molecular cell.

[14]  E. Lewis.  A gene complex controlling segmentation in Drosophila , 1978, Nature.

[15]  K. Helin,et al.  Maintaining cell identity: PRC2-mediated regulation of transcription and cancer , 2016, Nature Reviews Cancer.

[16]  D. Reinberg,et al.  Role of the polycomb protein EED in the propagation of repressive histone marks , 2009, Nature.

[17]  Elizabeth T. Wiles,et al.  H3K27 methylation: a promiscuous repressive chromatin mark. , 2017, Current opinion in genetics & development.

[18]  Chen Davidovich,et al.  The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2 , 2015, RNA.

[19]  D. Reinberg,et al.  Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin. , 2014, Molecular cell.

[20]  C. Allis,et al.  Polycomb Group proteins: an evolutionary perspective. , 2007, Trends in genetics : TIG.

[21]  Yukihide Tomari,et al.  Cryptic RNA-binding by PRC2 components EZH2 and SUZ12 , 2015, RNA biology.

[22]  T. Cech,et al.  Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA , 2017, Nature Structural & Molecular Biology.

[23]  R. Margueron,et al.  Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation , 2015, Molecular cell.

[24]  S. Orkin,et al.  Targeted Disruption of the EZH2/EED Complex Inhibits EZH2-dependent Cancer , 2013, Nature chemical biology.

[25]  Wendy A Bickmore,et al.  Ring1B compacts chromatin structure and represses gene expression independent of histone ubiquitination. , 2010, Molecular cell.

[26]  X. Zhou,et al.  Dense Chromatin Activates Polycomb Repressive Complex 2 to Regulate H3 Lysine 27 Methylation , 2012, Science.

[27]  D. Reinberg,et al.  The Polycomb complex PRC2 and its mark in life , 2011, Nature.

[28]  Uma M. Muthurajan,et al.  The role of the nucleosome acidic patch in modulating higher order chromatin structure , 2013, Journal of The Royal Society Interface.

[29]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[30]  H. Bourbon,et al.  Genome Regulation by Polycomb and Trithorax: 70 Years and Counting , 2017, Cell.

[31]  K. Gajiwala,et al.  Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance , 2016, Nature Communications.

[32]  E. Blanco,et al.  EPOP Functionally Links Elongin and Polycomb in Pluripotent Stem Cells. , 2016, Molecular cell.

[33]  Xin Liu,et al.  Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2 , 2015, Science.

[34]  A. Bauer,et al.  Histone methylation by PRC2 is inhibited by active chromatin marks. , 2011, Molecular cell.

[35]  E. Nogales,et al.  Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes , 2018, Nature Structural & Molecular Biology.

[36]  D. Reinberg,et al.  Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin , 2013, Genes & development.

[37]  D. Reinberg,et al.  PRC2 binds to active promoters and contacts nascent RNAs in embryonic stem cells , 2013, Nature Structural &Molecular Biology.

[38]  J. Bonanno,et al.  Structural Context of Disease-Associated Mutations and Putative Mechanism of Autoinhibition Revealed by X-Ray Crystallographic Analysis of the EZH2-SET Domain , 2013, PloS one.

[39]  Jon R. Wilson,et al.  Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2 , 2016, Nature Communications.

[40]  J. Chai,et al.  Structural basis of EZH2 recognition by EED. , 2007, Structure.

[41]  Arend Sidow,et al.  Jarid2/Jumonji Coordinates Control of PRC2 Enzymatic Activity and Target Gene Occupancy in Pluripotent Cells , 2009, Cell.

[42]  Xin Liu,et al.  Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding. , 2018, Molecular cell.

[43]  R. Aebersold,et al.  Structures of human PRC2 with its cofactors AEBP2 and JARID2 , 2018, Science.

[44]  G. Robertson,et al.  A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers. , 2004, Gene.

[45]  Juri Rappsilber,et al.  JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells , 2010, Nature.

[46]  Gang Li,et al.  Jarid2 and PRC2, partners in regulating gene expression. , 2010, Genes & development.

[47]  Sabine Mueller,et al.  The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. , 2013, Genes & development.

[48]  M. King,et al.  Characterization of EZH1, a human homolog of Drosophila Enhancer of zeste near BRCA1. , 1996, Genomics.