Polycomb repressive complex
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BACKGROUND: Polycomb repressive complexes 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; Polycomb repressive complex 1 catalyzes the monoubiquitination of histone H2A at lysine 119. Both complexes have been thoroughly studied in Arabidopsis, but the evolution of polycomb group gene families in monocots, particularly those with complex allopolyploid origins, is unknown. RESULTS: Here, we present the in silico identification of the Polycomb repressive complex 1 and 2 (PRC2, PRC1) subunits in allohexaploid bread wheat, the reconstruction of their evolutionary history and a transcriptional analysis over a series of 33 developmental stages. We identified four main subunits of PRC2 [E(z), Su(z), FIE and MSI] and three main subunits of PRC1 (Pc, Psc and Sce) and determined their chromosomal locations. We found that most of the genes coding for subunit proteins are present as paralogs in bread wheat. Using bread wheat RNA-seq data from different tissues and developmental stages throughout plant ontogenesis revealed variable transcriptional activity for individual paralogs. Phylogenetic analysis showed a high level of protein conservation among temperate cereals. CONCLUSIONS: 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.
- MeSH
- chromozomy rostlin MeSH
- fylogeneze MeSH
- mapování chromozomů MeSH
- molekulární evoluce MeSH
- počítačová simulace MeSH
- PRC1 genetika MeSH
- PRC2 genetika MeSH
- pšenice genetika MeSH
- RNA rostlin MeSH
- sekvenování transkriptomu MeSH
- stanovení celkové genové exprese MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND INFORMATION: A Polycomb (PcG) body is an orphan nuclear subcompartment characterised by accumulations of Polycomb repressive complex 1 (PRC1) proteins. However, seemingly contradictory reports have appeared that describe the PcG bodies either as protein-based bodies in the interchromatin compartment or chromatin domains. In this respect, molecular crowding is an important factor for the assembly and stability of nuclear subcompartments. In order to settle this contradiction, crowding experiments, that represent a convenient model distinguishing between interchromatin and chromatin compartments, were carried out. RESULTS: In sucrose-hypertonically induced crowding, we observed in U-2 OS cells that PcG bodies disappeared, but persisted as nuclear domains characterised by accumulations of DNA. This phenomenon was also observed in cells hypertonically treated with sorbitol and NaCl. Importantly, the observed changes were quickly reversible after re-incubation of cells in normal medium. We found that the PcG foci disappearance and the dissociation of PRC1 proteins (BMI1 and RING1a proteins) from chromatin were associated with their hyper-phosphorylation. In addition, under hyper- and hypotonic conditions, the behaviour of the PcG bodies differed from that of the typical nucleoplasmic body. CONCLUSION: PRC1 proteins accumulations do not represent a genuine nuclear subcompartment. The PcG body is a chromosomal domain, rather than a nucleoplasmic body.
- MeSH
- anthrachinony metabolismus MeSH
- barvení a značení MeSH
- chromatin metabolismus MeSH
- fluorescence MeSH
- fosforylace účinky léků MeSH
- genetická transkripce účinky léků MeSH
- hypertonické roztoky farmakologie MeSH
- lidé MeSH
- makromolekulární látky metabolismus MeSH
- nádorové buněčné linie MeSH
- polycomb proteiny metabolismus MeSH
- PRC1 metabolismus MeSH
- RNA genetika metabolismus MeSH
- sacharosa farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The spatial organization of the cell nucleus into separated domains with a specific macromolecular composition seems to be the fundamental principle that regulates its functioning. Because of the importance of regulation at the nuclear level, the cell nucleus and its domains have been intensively studied. This review is focused on the nuclear domain termed the Polycomb (PcG) body. We summarize and discuss data reported in the literature on different components of the PcG body that could form its structural basis. First, we describe the protein nature of the PcG body and the gene silencing factory model. Second, we review the target genes of Polycomb-mediated silencing and discuss their essentiality for the structural nature of the PcG body. In this respect, two different schematic models are presented. Third, we mention new data on the importance of RNAs, insulator elements and insulator proteins for the structure of PcG bodies. With this review, we hope to illustrate the importance of understanding the nature of the PcG subcompartment. The structural basis of a subcompartment directly reflects its status in the cell nucleus and the mechanism of its function.
Polycomb repressive complexes maintain transcriptional repression of genes encoding crucial developmental regulators through chromatin modification. Here we investigated the role of Polycomb repressive complex 2 (PRC2) in retinal development by inactivating its key components Eed and Ezh2. Conditional deletion of Ezh2 resulted in a partial loss of PRC2 function and accelerated differentiation of Müller glial cells. In contrast, inactivation of Eed led to the ablation of PRC2 function at early postnatal stage. Cell proliferation was reduced and retinal progenitor cells were significantly decreased in this mutant, which subsequently caused depletion of Müller glia, bipolar, and rod photoreceptor cells, primarily generated from postnatal retinal progenitor cells. Interestingly, the proportion of amacrine cells was dramatically increased at postnatal stages in the Eed-deficient retina. In accordance, multiple transcription factors controlling amacrine cell differentiation were upregulated. Furthermore, ChIP-seq analysis showed that these deregulated genes contained bivalent chromatin (H3K27me3+ H3K4me3+). Our results suggest that PRC2 is required for proliferation in order to maintain the retinal progenitor cells at postnatal stages and for retinal differentiation by controlling amacrine cell generation.
- MeSH
- buněčná diferenciace fyziologie MeSH
- chromatin metabolismus MeSH
- EZH2 protein metabolismus MeSH
- histony metabolismus MeSH
- kmenové buňky cytologie metabolismus MeSH
- metylace MeSH
- myši MeSH
- neurogeneze MeSH
- neuroglie metabolismus MeSH
- PRC2 metabolismus MeSH
- proliferace buněk MeSH
- retina metabolismus fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Východiska: Výzkum posledního desetiletí potvrdil význam epigenetických procesů při vzniku, vývoji a léčbě nádorových onemocnění. Především sekvenování nové generace umožnilo zmapovat lidský epigenom a sledovat jeho změny během kancerogeneze. Tento přístup odhalil přímá napojení epigenetických abnormalit na mutace genů, které kontrolují metylaci DNA, sbalování a funkci DNA v chromatinu, nebo na metabolizmus buněk. Epigenetické změny DNA se vyskytují už v časných fázích vývoje nádorových onemocnění, a jsou tedy slibnými kandidáty na diagnostické a prognostické markery a současně epigenetické procesy představují vhodné cíle pro vývoj nových terapeutických látek. Získané poznatky o aberantní metylaci DNA umožňují dva různé pohledy na to, jak daná modifikace přispívá k vývoji nádorového onemocnění. První pohled předpokládá, že normální buňky podléhají transformaci vlivem řídicích mutací, kdy následné metylace de novo a demetylace DNA přispívají k řadě programových změn genové exprese. Alternativní přístup pohlíží na změny v metylaci DNA jako na důsledek např. stárnutí buněk. A právě tyto získané změny zvyšují citlivost DNA ke vzniku mutací a k následné onkogenní transformaci. Cíle: Cílem přehledového článku je shrnout dosud známé úlohy abnormální metylace DNA při vývoji nádorového onemocnění a představit již publikovanou alternativní teorii, která k dané problematice přistupuje méně obvyklým způsobem.
Background: Research in the last decade has confirmed the importance of epigenetic processes for the onset, development, and treatment of cancer. Next generation sequencing has allowed the inspection and mapping of the human epigenome and its monitoring for changes during carcinogenesis, which has revealed direct links between epigenetic abnormalities and mutations in genes that control DNA methylation and packing and those that function in chromatin dynamics and metabolism. Epigenetic changes that occur in the early stages of tumor progression thus represent promising candidates for diagnostic and prognostic markers, and epigenetic processes are suitable targets for the development of new therapeutic strategies. There are two contrasting views on how aberrant DNA methylation contributes to the development of cancer. The first view assumes that normal cells undergo transformation due to driver mutations and subsequent de novo methylation and DNA demethylation, resulting in global changes in gene expression. The second view considers changes in DNA methylation to be a consequence of cell aging, for example, and that the acquired changes increase the sensitivity of DNA to mutations and oncogenic transformation. Aims: The aim of the review article is to briefly summarize the role of abnormal DNA methylation in the development of cancer, and to present an alternative theory that considers the role of aberrant DNA methylation patterns in cancer from a new and unconventional perspective.
- Klíčová slova
- geny Bmi1 a Ezh2, proteiny rodiny PcG,
- MeSH
- exprese genu * genetika imunologie účinky léků MeSH
- imunohistochemie metody trendy využití MeSH
- klinické laboratorní techniky metody využití MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- nádorové buněčné linie mikrobiologie účinky léků MeSH
- neuroektodermové nádory * diagnóza etiologie genetika MeSH
- polycomb proteiny genetika izolace a purifikace MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.
- MeSH
- adenosintrifosfatasy metabolismus MeSH
- chromatin chemie MeSH
- DNA-helikasy genetika MeSH
- dominantní geny * MeSH
- epigenomika MeSH
- genotyp MeSH
- heterozygot MeSH
- jaderné proteiny genetika MeSH
- kultivační média MeSH
- lidé MeSH
- missense mutace MeSH
- multivariační analýza MeSH
- mutace * MeSH
- myší embryonální kmenové buňky cytologie MeSH
- myši transgenní MeSH
- myši MeSH
- nádory genetika MeSH
- polycomb proteiny genetika MeSH
- restrukturace chromatinu MeSH
- sekvenční analýza RNA MeSH
- transkripční faktory genetika MeSH
- zesilovače transkripce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Aberrant DNA methylation is an important cancer hallmark, yet the dynamics of DNA methylation changes in human carcinogenesis remain largely unexplored. Moreover, the role of DNA methylation for prediction of clinical outcome is still uncertain and confined to specific cancers. Here we perform the most comprehensive study of DNA methylation changes throughout human carcinogenesis, analysing 27,578 CpGs in each of 1,475 samples, ranging from normal cells in advance of non-invasive neoplastic transformation to non-invasive and invasive cancers and metastatic tissue. We demonstrate that hypermethylation at stem cell PolyComb Group Target genes (PCGTs) occurs in cytologically normal cells three years in advance of the first morphological neoplastic changes, while hypomethylation occurs preferentially at CpGs which are heavily Methylated in Embryonic Stem Cells (MESCs) and increases significantly with cancer invasion in both the epithelial and stromal tumour compartments. In contrast to PCGT hypermethylation, MESC hypomethylation progresses significantly from primary to metastatic cancer and defines a poor prognostic signature in four different gynaecological cancers. Finally, we associate expression of TET enzymes, which are involved in active DNA demethylation, to MESC hypomethylation in cancer. These findings have major implications for cancer and embryonic stem cell biology and establish the importance of systemic DNA hypomethylation for predicting prognosis in a wide range of different cancers.
- MeSH
- CpG ostrůvky genetika MeSH
- DNA vazebné proteiny genetika MeSH
- dospělí MeSH
- embryonální kmenové buňky * cytologie metabolismus MeSH
- epigeneze genetická MeSH
- hematopoetické kmenové buňky cytologie metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA * genetika MeSH
- nádorová transformace buněk * genetika MeSH
- nádorové kmenové buňky * cytologie metabolismus MeSH
- nádory * genetika metabolismus MeSH
- polycomb proteiny MeSH
- prognóza * MeSH
- promotorové oblasti (genetika) MeSH
- protoonkogenní proteiny genetika MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny * genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Polycomb repressive complex 2 (PRC2) is involved in maintaining transcriptionally silent chromatin states through methylating lysine 27 of histone H3 by the catalytic subunit enhancer of zeste [E(z)]. 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. For the first time, we identify the putative ortholog of E(z) in Discoba, a lineage hypothetically proximal to the eukaryotic root, strongly supporting emergence of PRC2 before the diversification of eukaryotes. Analyzing 283 species, we robustly detect a common presence of E(z) and ESC, indicating a conserved functional core. Full-length Su(z)12 orthologs were identified in some lineages and species only, indicating, nonexclusively, high divergence of VEFS-Box-containing Su(z)12-like proteins, functional convergence of sequence-unrelated proteins, or Su(z)12 dispensability. Our results trace E(z) evolution within the SET-domain protein family, proposing a substrate specificity shift during E(z) evolution based on SET-domain and H3 histone interaction prediction.
