scholarly journals Inhibition of Polycomb Repressive Complex 2 activity reduces trimethylation of H3K27 and affects development in Arabidopsis seedlings

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Veronica Ruta ◽  
Chiara Longo ◽  
Alessandra Boccaccini ◽  
Valentina Noemi Madia ◽  
Francesco Saccoliti ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Transcriptional Control ◽  
Catalytic Subunit ◽  
Human Leukemia ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Human Leukemia Cells ◽  
Suitable Target ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract Background Polycomb repressive complex 2 (PRC2) is an epigenetic transcriptional repression system, whose catalytic subunit (ENHANCER OF ZESTE HOMOLOG 2, EZH2 in animals) is responsible for trimethylating histone H3 at lysine 27 (H3K27me3). In mammals, gain-of-function mutations as well as overexpression of EZH2 have been associated with several tumors, therefore making this subunit a suitable target for the development of selective inhibitors. Indeed, highly specific small-molecule inhibitors of EZH2 have been reported. In plants, mutations in some PRC2 components lead to embryonic lethality, but no trial with any inhibitor has ever been reported. Results We show here that the 1,5-bis (3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one compound (RDS 3434), previously reported as an EZH2 inhibitor in human leukemia cells, is active on the Arabidopsis catalytic subunit of PRC2, since treatment with the drug reduces the total amount of H3K27me3 in a dose-dependent fashion. Consistently, we show that the expression level of two PRC2 targets is significantly increased following treatment with the RDS 3434 compound. Finally, we show that impairment of H3K27 trimethylation in Arabidopsis seeds and seedlings affects both seed germination and root growth. Conclusions Our results provide a useful tool for the plant community in investigating how PRC2 affects transcriptional control in plant development.

scholarly journals Phylogenetic profiling suggests early origin of the core subunits of Polycomb Repressive Complex 2 (PRC2)

2021 ◽  
Author(s):  
Abdoallah Sharaf ◽  
Mallika Vijayanathan ◽  
Miroslav Obornik ◽  
iva Mozgova
Keyword(s):  
Developmental Regulation ◽  
Structural Diversity ◽  
Polycomb Group ◽  
Catalytic Subunit ◽  
Set Domain ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Domains Of Life ◽  
Domain Protein ◽  
Phylogenetic Profiling

Polycomb Repressive Complex 2 (PRC2) is involved in establishing transcriptionally silent chromatin states through its ability to methylate lysine 27 of histone H3 by the catalytic subunit Enhancer of zeste [E(z)]. Polycomb group (PcG) proteins play a crucial role in the maintenance of cell identity and in developmental regulation. Previously, the diversity of PRC2 subunits within some eukaryotic lineages has been reported and its presence in early eukaryotic evolution has been hypothesized. So far however, systematic survey of the presence of PRC2 subunits in species of all eukaryotic lineages is missing. Here, we report the diversity of PRC2 core subunit proteins in different eukaryotic supergroups with emphasis on the early-diverged lineages and explore the molecular evolution of PRC2 subunits by phylogenetics. In detail, we investigate the SET-domain protein sequences and their evolution across the four domains of life and particularly focus on the structural diversity of the SET-domain subfamily containing E(z), the catalytic subunit of PRC2. We show that PRC2 subunits are already present in early eukaryotic lineages, strengthening the support for PRC2 emergence prior to diversification of eukaryotes. We identify a common presence of E(z) and ESC, suggesting that Su(z)12 may have emerged later and/or may be dispensable from the evolutionarily conserved functional core of PRC2. Furthermore, our results broaden our understanding of the E(z) evolution within the SET-domain protein family, suggesting possibilities of function evolution. Through this, we shed light on a possible emerging point of the PRC2 and the evolution of its function in eukaryotes.

scholarly journals Zebrafish Polycomb repressive complex-2 critical roles are largely Ezh2- over Ezh1-driven and concentrate during early embryogenesis

2021 ◽  
Author(s):  
Gabriel A. Yette ◽  
Scott Stewart ◽  
Kryn Stankunas
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Axial Skeleton ◽  
Early Embryogenesis ◽  
Loss Of Function ◽  
Allelic Series ◽  
Polycomb Repressive Complex ◽  
Genetic Studies ◽  
Polycomb Repressive Complex 2 ◽  
Early Developmental

ABSTRACTPolycomb repressive complex-2 (PRC2) methylation of histone H3 lysine-27 (H3K27me) is associated with stable transcriptional repression. PRC2 famously silences Hox genes to maintain anterior-posterior segment identities but also enables early cell fate specification, restrains progenitor cell differentiation, and canalizes cell identities. Zebrafish PRC2 genetic studies have focused on ezh2, which, with its paralog ezh1, encodes the H3K27 methyltransferase component. ezh2 loss-of-function mutants reinforce essential vertebrate PRC2 functions during early embryogenesis albeit with limited contributions to body plan establishment. However, redundancy with ezh1 and the lethality of maternal-zygotic homozygous ezh2 nulls could obscure additional early developmental and organogenesis roles of PRC2. Here, we combine new and existing zebrafish ezh1 and ezh2 alleles to show collective maternal/zygotic ezh2 exclusively provides earliest embryonic PRC2 H3K27me3 activity. Zygotic ezh1, which becomes progressively expressed as ezh2 levels dissipate, has minor redundant and noncompensatory larval roles but itself is not required for viability or fertility. Zygotic Ezh2/PRC2 promotes correct craniofacial bone shape and size by maintaining proliferative pre-osteoblast pools. An ezh2 allelic series including disrupted maternal ezh2 uncovers axial skeleton homeotic transformations and pleiotropic organogenesis defects. Further, once past a critical early window, we show zebrafish can develop near normally with minimal bulk H3K27me3. Our results suggest Ezh2-containing PRC2 stabilizes rather than instructs early developmental decisions while broadly contributing to organ size and embellishment.

scholarly journals Loss of Polycomb Repressive Complex 2 Function Alters Digestive Organ Homeostasis and Neuronal Differentiation in Zebrafish

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3142
Author(s):  
Ludivine Raby ◽  
Pamela Völkel ◽  
Shaghayegh Hasanpour ◽  
Julien Cicero ◽  
Robert-Alain Toillon ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Transcriptional Repression ◽  
Loss Of Function ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Gene Coding ◽  
Development And Differentiation ◽  
Cellular Identity ◽  
The Brain

Polycomb repressive complex 2 (PRC2) mediates histone H3K27me3 methylation and the stable transcriptional repression of a number of gene expression programs involved in the control of cellular identity during development and differentiation. Here, we report on the generation and on the characterization of a zebrafish line harboring a null allele of eed, a gene coding for an essential component of the PRC2. Homozygous eed-deficient mutants present a normal body plan development but display strong defects at the level of the digestive organs, such as reduced size of the pancreas, hepatic steatosis, and a loss of the intestinal structures, to die finally at around 10–12 days post fertilization. In addition, we found that PRC2 loss of function impairs neuronal differentiation in very specific and discrete areas of the brain and increases larval activity in locomotor assays. Our work highlights that zebrafish is a suited model to study human pathologies associated with PRC2 loss of function and H3K27me3 decrease.

scholarly journals 15 Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and the Polycomb Repressive Complex 2

Apmis ◽  
2008 ◽  
Vol 116 (5) ◽  
pp. 424-424
Author(s):  
Diego Pasini ◽  
Klaus H. Hansen ◽  
Jesper Christensen ◽  
Karl Agger ◽  
Paul A. C. Cloos ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Coordinated Regulation

scholarly journals 15Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and the Polycomb Repressive Complex 2

Apmis ◽  
2008 ◽  
Vol 116 (5) ◽  
pp. 424-424
Author(s):  
Diego Pasini ◽  
Klaus H. Hansen ◽  
Jesper Christensen ◽  
Karl Agger ◽  
Paul A. C. Cloos ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2

scholarly journals A Functional Link between Nuclear RNA Decay and Transcriptional Control Mediated by the Polycomb Repressive Complex 2

Cell Reports ◽  
2019 ◽  
Vol 29 (7) ◽  
pp. 1800-1811.e6 ◽  
Author(s):  
William Garland ◽  
Itys Comet ◽  
Mengjun Wu ◽  
Aliaksandra Radzisheuskaya ◽  
Leonor Rib ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Rna Decay ◽  
Polycomb Repressive Complex ◽  
Functional Link ◽  
Polycomb Repressive Complex 2 ◽  
Nuclear Rna

scholarly journals A Class of Protein-Coding RNAs Binds to Polycomb Repressive Complex 2 and Alters Histone Methylation

2021 ◽  
Vol 11 ◽  
Author(s):  
Meijian Liao ◽  
Xiaolin Sun ◽  
Shoucui Gao ◽  
Yaou Zhang
Keyword(s):  
Network Analysis ◽  
Transcriptional Repression ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Rna Recognition Motif ◽  
Rna Recognition ◽  
Polycomb Repressive Complex ◽  
Protein Coding ◽  
Polycomb Repressive Complex 2 ◽  
Rna Immunoprecipitation

Polycomb repressive complex 2 (PRC2) is a multi-subunit protein complex mediating the methylation of lysine 27 on histone H3 and playing an important role in transcriptional repression during tumorigenesis and development. Previous studies revealed that both protein-coding and non-coding RNAs could bind to PRC2 complex. However, the functions of protein-coding RNAs that bind to PRC2 complex in tumor are still unknown. Through data mining and RNA immunoprecipitation (RIP) assay, our study found that there were a class of protein-coding RNAs bound to PRC2 complex and H3 with tri-methylation on lysine 27. The Bayesian gene regulatory network analysis pointed out that these RNAs regulated the expression of PRC2-regulated genes in cancer. In addition, gene set enrichment analysis (GSEA), gene ontology (GO) analysis, and weighted gene co-expression network analysis (WGCNA) also confirmed that these RNAs were associated with histone modification in cancer. We also confirmed that MYO1C, a PRC2-bound transcript, inhibited the modification level of H3K27me3. Further detailed study showed that TMEM117 regulated TSLP expression through EZH2-mediated H3K27me3 modification. Interestingly, the RNA recognition motif of PRC2 complex might help these RNAs bind to the PRC2 complex more easily. The same regulatory pattern was found in mice as well.

Abstract 4316: MCL-1 inhibition ameliorates the expansion of human leukemia in a dose dependent fashion

2017 ◽  
Author(s):  
Haley E. Ramsey ◽  
Melissa A. Fischer ◽  
Taekyu Lee ◽  
Agnieszka E. Gorska ◽  
Pia Arrate ◽  
...  
Keyword(s):  
Human Leukemia ◽  
Dose Dependent Fashion ◽  
Dose Dependent

scholarly journals Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2

2008 ◽  
Vol 22 (10) ◽  
pp. 1345-1355 ◽  
Author(s):  
D. Pasini ◽  
K. H. Hansen ◽  
J. Christensen ◽  
K. Agger ◽  
P. A.C. Cloos ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Coordinated Regulation

scholarly journals Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniel Grau ◽  
Yixiao Zhang ◽  
Chul-Hwan Lee ◽  
Marco Valencia-Sánchez ◽  
Jenny Zhang ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Conformational Change ◽  
Conformational Flexibility ◽  
Catalytic Subunit ◽  
Biological Functions ◽  
Polycomb Repressive Complex ◽  
Chromatin Compaction ◽  
Polycomb Repressive Complex 2 ◽  
Selective Incorporation ◽  
Nucleosome Binding

AbstractPolycomb 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.

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