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 Association of BMI1 with Polycomb Bodies Is Dynamic and Requires PRC2/EZH2 and the Maintenance DNA Methyltransferase DNMT1

2005 ◽  
Vol 25 (24) ◽  
pp. 11047-11058 ◽  
Author(s):  
Inmaculada Hernández-Muñoz ◽  
Panthea Taghavi ◽  
Coenraad Kuijl ◽  
Jacques Neefjes ◽  
Maarten van Lohuizen
Keyword(s):  
Dna Methyltransferase ◽  
Pericentric Heterochromatin ◽  
Polycomb Group ◽  
Gene Repression ◽  
Kinetic Properties ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Nuclear Structures ◽  
Stable Maintenance ◽  
Polycomb Bodies

ABSTRACT Polycomb group (PcG) proteins are epigenetic chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized. Polycomb repressive complex 2 (PRC2) is thought to be involved in the initiation of gene silencing, whereas Polycomb repressive complex 1 (PRC1) is implicated in the stable maintenance of gene repression. Here, we investigate the kinetic properties of the binding of one of the PRC1 core components, BMI1, with PcG bodies. PcG bodies are unique nuclear structures located on regions of pericentric heterochromatin, found to be the site of accumulation of PcG complexes in different cell lines. We report the presence of at least two kinetically different pools of BMI1, a highly dynamic and a less dynamic fraction, which may reflect BMI1 pools with different binding capacities to these stable heterochromatin domains. Interestingly, PRC2 members EED and EZH2 appear to be essential for BMI1 recruitment to the PcG bodies. Furthermore, we demonstrate that the maintenance DNA methyltransferase DNMT1 is necessary for proper PcG body assembly independent of DNMT-associated histone deacetylase activity. Together, these results provide new insights in the mechanism for regulation of chromatin silencing by PcG proteins and suggest a highly regulated recruitment of PRC1 to chromatin.

scholarly journals The histone variant H2A.Z is required to establish normal patterns of H3K27 methylation in Neurospora crassa

2020 ◽  
Author(s):  
Abigail J. Courtney ◽  
Masayuki Kamei ◽  
Aileen R. Ferraro ◽  
Kexin Gai ◽  
Qun He ◽  
...  
Keyword(s):  
Neurospora Crassa ◽  
Molecular Mechanisms ◽  
Histone Variant ◽  
Polycomb Group ◽  
Stable Gene ◽  
Polycomb Group Proteins ◽  
Polycomb Repressive Complex ◽  
Facultative Heterochromatin ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation

ABSTRACTNeurospora crassa contains a minimal Polycomb repression system, which provides rich opportunities to explore Polycomb-mediated repression across eukaryotes and enables genetic studies that can be difficult in plant and animal systems. Polycomb Repressive Complex 2 is a multi-subunit complex that deposits mono-, di-, and tri-methyl groups on lysine 27 of histone H3, and tri-methyl H3K27 is a molecular marker of transcriptionally repressed facultative heterochromatin. In mouse embryonic stem cells and multiple plant species, H2A.Z has been found to be co-localized with H3K27 methylation. H2A.Z is required for normal H3K27 methylation in these experimental systems, though the regulatory mechanisms are not well understood. We report here that Neurospora crassa mutants lacking H2A.Z or SWR-1, the ATP-dependent histone variant exchanger, exhibit a striking reduction in levels of H3K27 methylation. RNA-sequencing revealed downregulation of eed, encoding a subunit of PRC2, in an hH2Az mutant compared to wild type and overexpression of EED in a ΔhH2Az;Δeed background restored most H3K27 methylation. Reduced eed expression leads to region-specific losses of H3K27 methylation suggesting that EED-dependent mechanisms are critical for normal H3K27 methylation at certain regions in the genome.AUTHOR SUMMARYEukaryotic DNA is packaged with histone proteins to form a DNA-protein complex called chromatin. Inside the nucleus, chromatin can be assembled into a variety of higher-order structures that profoundly impact gene expression. Polycomb Group proteins are important chromatin regulators that control assembly of a highly condensed form of chromatin. The functions of Polycomb Group proteins are critical for maintaining stable gene repression during development of multicellular organisms, and defects in Polycomb proteins are linked to disease. There is significant interest in elucidating the molecular mechanisms that regulate the activities of Polycomb Group proteins and the assembly of transcriptionally repressed chromatin domains. In this study, we used a model fungus to investigate the regulatory relationship between a histone variant, H2A.Z, and a conserved histone modifying enzyme complex, Polycomb Repressive Complex 2 (PRC2). We found that H2A.Z is required for normal expression of a PRC2 component. Mutants that lack H2A.Z have defects in chromatin structure at some parts of the genome, but not others. Identification of PRC2-target domains that are differentially dependent on EED provides insights into the diverse mechanisms that regulate assembly and maintenance of facultative heterochromatin in a simple model system.Data Reference NumbersGSE146611

scholarly journals Dominant Alleles Identify SET Domain Residues Required for Histone Methyltransferase of Polycomb Repressive Complex 2

2008 ◽  
Vol 283 (41) ◽  
pp. 27757-27766 ◽  
Author(s):  
Preeti Joshi ◽  
Elizabeth A. Carrington ◽  
Liangjun Wang ◽  
Carrie S. Ketel ◽  
Ellen L. Miller ◽  
...  
Keyword(s):  
Histone Methyltransferase ◽  
Set Domain ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2

scholarly journals Identification of Polycomb Repressive Complex 1 and 2 Core Components in Hexaploid Bread Wheat

2019 ◽  
Author(s):  
Beáta Strejčková ◽  
Radim Čegan ◽  
Ales Pecinka ◽  
Zbyněk Milec ◽  
Jan Šafář
Keyword(s):  
Bread Wheat ◽  
Developmental Stages ◽  
Gene Families ◽  
Polycomb Group ◽  
Transcriptional Analysis ◽  
Histone H2a ◽  
Polycomb Repressive Complex ◽  
Polycomb Repressive Complex 2 ◽  
Core Components ◽  
Polycomb Repressive Complex 1

ABSTRACTPolycomb repressive complex 1 and 2 play important roles in epigenetic gene regulation by posttranslationally modifying specific histone residues. Polycomb repressive complex 2 is responsible for the trimethylation of lysine 27 on histone H3, while Polycomb repressive complex 1 catalyzes the monoubiquitination of histone H2A at lysine 119. Although these biochemical functions are evolutionarily conserved, studies in animals and plants, mainly Arabidopsis thaliana, showed that specific subunits have evolved into small gene families, with individual members acting at different developmental stages or responding to specific environmental stimuli. However, the evolution of polycomb group gene families in monocots, particularly those with complex allopolyploid origins, is unknown. Here, we present the in silico identification of the Polycomb repressive complex 1 and 2 subunits in allohexaploid bread wheat, the reconstruction of their evolutionary history and a transcriptional analysis over a series of 33 developmental stages. The identification and chromosomal location of the Polycomb repressive complex 1 and 2 core components in bread wheat may enable a deeper understanding of developmental processes, including vernalization in commonly grown winter wheat.

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 Bmi1 – A Path to Targeting Cancer Stem Cells

2017 ◽  
Vol 13 (02) ◽  
pp. 147 ◽  
Author(s):  
David Bakhshinyan ◽  
Ashley A Adile ◽  
Chitra Venugopal ◽  
Sheila K Singh ◽  
◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Translational Regulation ◽  
Tumour Progression ◽  
Metastatic Potential ◽  
Polycomb Group ◽  
Polycomb Repressive Complex ◽  
Self Renewal ◽  
Polycomb Repressive Complex 2 ◽  
Wide Range

The Polycomb group (PcG) genes encode for proteins comprising two multiprotein complexes, Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2). Although the initial discovery of PcG genes was made in Drosophila, as transcriptional repressors of homeotic (HOX) genes. Polycomb repressive complexes have been since implicated in regulating a wide range of cellular processes, including differentiation and self-renewal in normal and cancer stem cells. Bmi1, a subunit of PRC1, has been long implicated in driving self-renewal, the key property of stem cells. Subsequent studies showing upregulation of Bmi1 in several cancers correlated with increased aggressiveness, radioresistance and metastatic potential, provided rationale for development of targeted therapies against Bmi1. Although Bmi1 activity can be reduced through transcriptional, post-transcriptional and post-translational regulation, to date, the most promising approach has been through small molecule inhibitors targeting Bmi1 activity. The post-translational targeting of Bmi1 in colorectal carcinoma, lung adenocarcinoma, multiple myeloma and medulloblastoma have led to significant reduction of self-renewal capacity of cancer stem cells, leading to slower tumour progression and reduced extent of metastatic spread. Further value of Bmi1 targeting in cancer can be established through trials evaluating the combinatorial effect of Bmi1 inhibition with current ‘gold standard’ therapies.

scholarly journals EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Roberta Ragazzini ◽  
Raquel Pérez-Palacios ◽  
Irem H. Baymaz ◽  
Seynabou Diop ◽  
Katia Ancelin ◽  
...  
Keyword(s):  
Polycomb Group ◽  
Initial Number ◽  
Core Complex ◽  
Polycomb Repressive Complex ◽  
Inhibitory Protein ◽  
Polycomb Repressive Complex 2 ◽  
The Core ◽  
Accessory Subunits ◽  
Global Increase ◽  
Late Stages

Abstract The Polycomb group of proteins is required for the proper orchestration of gene expression due to its role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip in mice leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This does not affect the initial number of follicles but is associated with a reduction of follicles in aging. Our results suggest that mature oocytes Ezhip−/− might not be fully functional and indicate that fertility is strongly impaired in Ezhip−/− females. Altogether, our study uncovers EZHIP as a regulator of chromatin landscape in gametes.

scholarly journals The N Terminus of Drosophila ESC Binds Directly to Histone H3 and Is Required for E(Z)-Dependent Trimethylation of H3 Lysine 27

2007 ◽  
Vol 27 (6) ◽  
pp. 2014-2026 ◽  
Author(s):  
Feng Tie ◽  
Carl A. Stratton ◽  
Rebeccah L. Kurzhals ◽  
Peter J. Harte
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Histone H3 ◽  
Polycomb Group ◽  
Set Domain ◽  
Chromatin Immunoprecipitation Assay ◽  
Polycomb Repressive Complex 2 ◽  
Polycomb Response Element ◽  
Evolutionarily Conserved ◽  
Hmtase Activity ◽  
And Function

ABSTRACT Polycomb group proteins mediate heritable transcriptional silencing and function through multiprotein complexes that methylate and ubiquitinate histones. The 600-kDa E(Z)/ESC complex, also known as Polycomb repressive complex 2 (PRC2), specifically methylates histone H3 lysine 27 (H3 K27) through the intrinsic histone methyltransferase (HMTase) activity of the E(Z) SET domain. By itself, E(Z) exhibits no detectable HMTase activity and requires ESC for methylation of H3 K27. The molecular basis for this requirement is unknown. ESC binds directly, via its C-terminal WD repeats (β-propeller domain), to E(Z). Here, we show that the N-terminal region of ESC that precedes its β-propeller domain interacts directly with histone H3, thereby physically linking E(Z) to its substrate. We show that when expressed in stable S2 cell lines, an N-terminally truncated ESC (FLAG-ESC61-425), like full-length ESC, is incorporated into complexes with E(Z) and binds to a Ubx Polycomb response element in a chromatin immunoprecipitation assay. However, incorporation of this N-terminally truncated ESC into E(Z) complexes prevents trimethylation of histone H3 by E(Z). We also show that a closely related Drosophila melanogaster paralog of ESC, ESC-like (ESCL), and the mammalian homolog of ESC, EED, also interact with histone H3 via their N termini, indicating that the interaction of ESC with histone H3 is evolutionarily conserved, reflecting its functional importance. Our data suggest that one of the roles of ESC (and ESCL and EED) in PRC2 complexes is to enable E(Z) to utilize histone H3 as a substrate by physically linking enzyme and substrate.

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