Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structure, mechanism, and regulation of polycomb-repressive complex 2.

ABSTRACT: Polycomb repressive complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this Minireview, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, allosteric regulation, and inhibition by a class of small molecules that are currently undergoing cancer clinical trials. We conclude by exploring unresolved questions and future directions for inquiry regarding PRC2 structure and function.

SUBMITTER: Moritz LE

PROVIDER: S-EPMC6130931 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Structure, mechanism, and regulation of polycomb-repressive complex 2.

Moritz Lindsay E LE Trievel Raymond C RC

The Journal of biological chemistry 20170914 36

Polycomb repressive complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this Minireview, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, all ...[more]

PMID: 28912274

Similar Datasets

Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.

Project description:Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.

| S-EPMC4853478 | biostudies-literature

Huntingtin facilitates polycomb repressive complex 2.

Project description:Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in the huntingtin protein. Full-length huntingtin is thought to be a predominant HEAT repeat alpha-solenoid, implying a role as a facilitator of macromolecular complexes. Here we have investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex 2 (PRC2), suggested by shared embryonic deficiency phenotypes. Analysis of a set of full-length recombinant huntingtins, with different polyglutamine regions, demonstrated dramatic conformational flexibility, with an accessible hinge separating two large alpha-helical domains. Moreover, embryos lacking huntingtin exhibited impaired PRC2 regulation of Hox gene expression, trophoblast giant cell differentiation, paternal X chromosome inactivation and histone H3K27 tri-methylation, while full-length endogenous nuclear huntingtin in wild-type embryoid bodies (EBs) was associated with PRC2 subunits and was detected with trimethylated histone H3K27 at Hoxb9. Supporting a direct stimulatory role, full-length recombinant huntingtin significantly increased the histone H3K27 tri-methylase activity of reconstituted PRC2 in vitro, and structure-function analysis demonstrated that the polyglutamine region augmented full-length huntingtin PRC2 stimulation, both in Hdh(Q111) EBs and in vitro, with reconstituted PRC2. Knowledge of full-length huntingtin's alpha-helical organization and role as a facilitator of the multi-subunit PRC2 complex provides a novel starting point for studying PRC2 regulation, implicates this chromatin repressive complex in a neurodegenerative disorder and sets the stage for further study of huntingtin's molecular function and the impact of its modulatory polyglutamine region.

| S-EPMC2807366 | biostudies-literature

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

Project description: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.

| S-EPMC6438374 | biostudies-literature

Role of the Polycomb Repressive Complex 2 (PRC2) in Transcriptional Regulation and Cancer.

Project description:The chromatin environment is modulated by a machinery of chromatin modifiers, required for the specification and maintenance of cell fate. Many mutations in the machinery have been linked to the development and progression of cancer. In this review, we give a brief introduction to Polycomb group (PcG) proteins, their assembly into Polycomb repressive complexes (PRCs) and the normal physiological roles of these complexes with a focus on the PRC2. We review the many findings of mutations in the PRC2 coding genes, both loss-of-function and gain-of-function, associated with human cancers and discuss potential molecular mechanisms involved in the contribution of PRC2 mutations to cancer development and progression. Finally, we discuss some of the recent advances in developing and testing drugs targeting the PRC2 as well as emerging results from clinical trials using these drugs in the treatment of human cancers.

| S-EPMC5008062 | biostudies-literature

LATS2 Positively Regulates Polycomb Repressive Complex 2.

Project description:LATS2, a pivotal Ser/Thr kinase of the Hippo pathway, plays important roles in many biological processes. LATS2 also function in Hippo-independent pathway, including mitosis, DNA damage response and epithelial to mesenchymal transition. However, the physiological relevance and molecular basis of these LATS2 functions remain obscure. To understand novel functions of LATS2, we constructed a LATS2 knockout HeLa-S3 cell line using TAL-effector nuclease (TALEN). Integrated omics profiling of this cell line revealed that LATS2 knockout caused genome-wide downregulation of Polycomb repressive complex 2 (PRC2) and H3K27me3. Cell-cycle analysis revealed that downregulation of PRC2 was not due to cell cycle aberrations caused by LATS2 knockout. Not LATS1, a homolog of LATS2, but LATS2 bound PRC2 on chromatin and phosphorylated it. LATS2 positively regulates histone methyltransferase activity of PRC2 and their expression at both the mRNA and protein levels. Our findings reveal a novel signal upstream of PRC2, and provide insight into the crucial role of LATS2 in coordinating the epigenome through regulation of PRC2.

| S-EPMC4951031 | biostudies-literature

Polycomb repressive complex 1 controls uterine decidualization.

Project description:Uterine stromal cell decidualization is an essential part of the reproductive process. Decidual tissue development requires a highly regulated control of the extracellular tissue remodeling; however the mechanism of this regulation remains unknown. Through systematic expression studies, we detected that Cbx4/2, Rybp, and Ring1B [components of polycomb repressive complex 1 (PRC1)] are predominantly utilized in antimesometrial decidualization with polyploidy. Immunofluorescence analyses revealed that PRC1 members are co-localized with its functional histone modifier H2AK119ub1 (mono ubiquitination of histone-H2A at lysine-119) in polyploid cell. A potent small-molecule inhibitor of Ring1A/B E3-ubiquitin ligase or siRNA-mediated suppression of Cbx4 caused inhibition of H2AK119ub1, in conjunction with perturbation of decidualization and polyploidy development, suggesting a role for Cbx4/Ring1B-containing PRC1 in these processes. Analyses of genetic signatures by RNA-seq studies showed that the inhibition of PRC1 function affects 238 genes (154 up and 84 down) during decidualization. Functional enrichment analyses identified that about 38% genes primarily involved in extracellular processes are specifically targeted by PRC1. Furthermore, ~15% of upregulated genes exhibited a significant overlap with the upregulated Bmp2 null-induced genes in mice. Overall, Cbx4/Ring1B-containing PRC1 controls decidualization via regulation of extracellular gene remodeling functions and sheds new insights into underlying molecular mechanism(s) through transcriptional repression regulation.

| S-EPMC4867636 | biostudies-literature

Molecular Regulation of the Polycomb Repressive-Deubiquitinase.

Project description:Post-translational modification of histone proteins plays a major role in histone-DNA packaging and ultimately gene expression. Attachment of ubiquitin to the C-terminal tail of histone H2A (H2AK119Ub in mammals) is particularly relevant to the repression of gene transcription, and is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here, we outline recent advances in the understanding of PR-DUB regulation, which have come through structural studies of the Drosophila melanogaster PR-DUB, biochemical investigation of the human PR-DUB, and functional studies of proteins that associate with the PR-DUB. In humans, mutations in components of the PR-DUB frequently give rise to malignant mesothelioma, melanomas, and renal cell carcinoma, and increase disease risk from carcinogens. Diverse mechanisms may underlie disruption of the PR-DUB across this spectrum of disease. Comparing and contrasting the PR-DUB in mammals and Drosophila reiterates the importance of H2AK119Ub through evolution, provides clues as to how the PR-DUB is dysregulated in disease, and may enable new treatment approaches in cancers where the PR-DUB is disrupted.

| S-EPMC7660087 | biostudies-literature

Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2.

Project description:Myelination of peripheral nerves by Schwann cells requires coordinate regulation of gene repression as well as gene activation. Several chromatin remodeling pathways critical for peripheral nerve myelination have been identified, but the functions of histone methylation in the peripheral nerve have not been elucidated. To determine the role of histone H3 Lys27 methylation, we have generated mice with a Schwann cell-specific knock-out of Eed, which is an essential subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 Lys27. Analysis of this mutant revealed no significant effects on early postnatal development of myelin. However, its loss eventually causes progressive hypermyelination of small-diameter axons and apparent fragmentation of Remak bundles. These data identify the PRC2 complex as an epigenomic modulator of mature myelin thickness, which is associated with changes in Akt phosphorylation. Interestingly, we found that Eed inactivation causes derepression of several genes, e.g., Sonic hedgehog (Shh) and Insulin-like growth factor-binding protein 2 (Igfbp2), that become activated after nerve injury, but without activation of a primary regulator of the injury program, c-Jun. Analysis of the activated genes in cultured Schwann cells showed that Igfbp2 regulates Akt activation. Our results identify an epigenomic pathway required for establishing thickness of mature myelin and repressing genes that respond to nerve injury.

| S-EPMC4452560 | biostudies-literature

Polycomb Repressive Complex 2: a Dimmer Switch of Gene Regulation in Calvarial Bone Development.

Project description:Purpose of reviewEpigenetic regulation is a distinct mechanism of gene regulation that functions by modulating chromatin structure and accessibility. Polycomb Repressive Complex 2 (PRC2) is a conserved chromatin regulator that is required in the developing embryo to control the expression of key developmental genes. An emerging feature of PRC2 is that it not only allows for binary ON/OFF states of gene expression but can also modulate gene expression in feed-forward loops to change the outcome of gene regulatory networks. This striking feature of epigenetic modulation has improved our understanding of musculoskeletal development.Recent findingsRecent advances in mouse embryos unravel a range of phenotypes that demonstrate the tissue-specific, temporal, and spatial role of PRC2 during organogenesis and cell fate decisions in vivo. Here, we take a detailed view of how PRC2 functions during the development of calvarial bone and skin. Based on the emerging evidence, we propose that PRC2 serves as a "dimmer switch" to modulate gene expression of target genes by altering the expression of activators and inhibitors. This review highlights the findings from contemporary research that allow us to investigate the unique developmental potential of intramembranous calvarial bones.

| S-EPMC7467536 | biostudies-literature

Promiscuous RNA binding by Polycomb repressive complex 2.

Project description:Polycomb repressive complex 2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Long noncoding RNAs (lncRNAs) recruit PRC2 to chromatin, but the general role of RNA in maintaining repressed chromatin is unknown. Here we measure the binding constants of human PRC2 to various RNAs and find comparable affinity for human lncRNAs targeted by PRC2 as for irrelevant transcripts from ciliates and bacteria. PRC2 binding is size dependent, with lower affinity for shorter RNAs. In vivo, PRC2 predominantly occupies repressed genes; PRC2 is also associated with active genes, but most of those are not regulated by PRC2. These findings support a model in which PRC2's promiscuous binding to RNA transcripts allows it to scan for target genes that have escaped repression, thus leading to maintenance of the repressed state. Such RNAs may also provide a decoy for PRC2.

| S-EPMC3823624 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data