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https://www.readbyqxmd.com/read/28229514/mutations-in-genes-encoding-polycomb-repressive-complex-2-subunits-cause-weaver-syndrome
#1
Eri Imagawa, Ken Higashimoto, Yasunari Sakai, Chikahiko Numakura, Nobuhiko Okamoto, Satoko Matsunaga, Akihide Ryo, Yoshinori Sato, Masafumi Sanefuji, Kenji Ihara, Yui Takada, Gen Nishimura, Hirotomo Saitsu, Takeshi Mizuguchi, Satoko Miyatake, Mitsuko Nakashima, Noriko Miyake, Hidenobu Soejima, Naomichi Matsumoto
Weaver syndrome is a rare congenital overgrowth disorder caused by heterozygous mutations in EZH2 (enhancer of zeste homolog 2) or EED (embryonic ectoderm development). EZH2 and EED are core components of the polycomb repressive complex 2 (PRC2), which possesses histone methyltransferase activity and catalyzes trimethylation of histone H3 at lysine 27. Here, we analyzed eight probands with clinically suspected Weaver syndrome by whole exome sequencing and identified three mutations: a 25.4-kb deletion partially involving EZH2 and CUL1 (individual 1), a missense mutation (c...
February 22, 2017: Human Mutation
https://www.readbyqxmd.com/read/28228691/overexpression-of-suppressor-of-zest-12-is-associated-with-cervical-node-metastasis-and-unfavorable-prognosis-in-tongue-squamous-cell-carcinoma
#2
Huijun Hu, Yi Wang, Zhongwu Li, Yumin Zhu, Wei Zhang, Dongmiao Wang, Tangyi Lin, Jianrong Yang, Yanling Wang, Jie Cheng
OBJECTIVE: Increased expression of suppressor of zest 12 (SUZ12), a core component of the polycomb repressive complex 2, contributes to human tumorigenesis and associates with patient prognosis. In the present study, we sought to investigate the expression of SUZ12 and its clinicopathological significance in primary tongue squamous cell carcinoma (TSCC). METHODS: The expression of SUZ12 protein was determined by immunohistochemistry in clinical samples from a retrospective cohort of 72 patients with primary TSCC who were treated at our institution from Jan...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28228601/loss-of-tumor-suppressor-kdm6a-amplifies-prc2-regulated-transcriptional-repression-in-bladder-cancer-and-can-be-targeted-through-inhibition-of-ezh2
#3
Lian Dee Ler, Sujoy Ghosh, Xiaoran Chai, Aye Aye Thike, Hong Lee Heng, Ee Yan Siew, Sucharita Dey, Liang Kai Koh, Jing Quan Lim, Weng Khong Lim, Swe Swe Myint, Jia Liang Loh, Pauline Ong, Xin Xiu Sam, Dachuan Huang, Tony Lim, Puay Hoon Tan, Sanjanaa Nagarajan, Christopher Wai Sam Cheng, Henry Ho, Lay Guat Ng, John Yuen, Po-Hung Lin, Cheng-Keng Chuang, Ying-Hsu Chang, Wen-Hui Weng, Steven G Rozen, Patrick Tan, Caretha L Creasy, See-Tong Pang, Michael T McCabe, Song Ling Poon, Bin Tean Teh
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type...
February 22, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28225770/a-distal-intergenic-region-controls-pancreatic-endocrine-differentiation-by-acting-as-a-transcriptional-enhancer-and-as-a-polycomb-response-element
#4
Joris van Arensbergen, Sebastien Dussaud, Corinne Pardanaud-Glavieux, Javier García-Hurtado, Claire Sauty, Aline Guerci, Jorge Ferrer, Philippe Ravassard
Lineage-selective expression of developmental genes is dependent on the interplay between activating and repressive mechanisms. Gene activation is dependent on cell-specific transcription factors that recognize transcriptional enhancer sequences. Gene repression often depends on the recruitment of Polycomb group (PcG) proteins, although the sequences that underlie the recruitment of PcG proteins, also known as Polycomb response elements (PREs), remain poorly understood in vertebrates. While distal PREs have been identified in mammals, a role for positive-acting enhancers in PcG-mediated repression has not been described...
2017: PloS One
https://www.readbyqxmd.com/read/28225203/identification-of-interacting-proteins-of-the-tafve-protein-involved-in-spike-development-in-bread-wheat
#5
Yong-Sheng Zheng, Yu-Qing Lu, Ying-Ying Meng, Rong-Zhi Zhang, Han Zhang, Jia-Mei Sun, Mu-Mu Wang, Li-Hui Li, Ru-Yu Li
FVE/MSI4 plays important roles in determining flowering time in Arabidopsis. However, its function is unexplored in wheat. In the present study, Co-IP and nano-LC-MS/MS were used to identify TaFVE-interacting or associated proteins. Altogether 89 differentially expressed proteins showed the same down-regulated expression trends as TaFVE in wheat line 5660M. Among them, 62 proteins were further predicted to be involved in the interaction network of TaFVE and 11 proteins have been shown to be potential TaFVE interactors based on curated databases and experimentally determined in other species by the STRING...
February 22, 2017: Proteomics
https://www.readbyqxmd.com/read/28223321/a-non-canonical-function-of-ezh2-preserves-immune-homeostasis
#6
Ajithkumar Vasanthakumar, Dakang Xu, Aaron Tl Lun, Andrew J Kueh, Klaas Pjm van Gisbergen, Nadia Iannarella, Xiaofang Li, Liang Yu, Die Wang, Bryan Rg Williams, Stanley Cw Lee, Ian J Majewski, Dale I Godfrey, Gordon K Smyth, Warren S Alexander, Marco J Herold, Axel Kallies, Stephen L Nutt, Rhys S Allan
Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T (NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3...
February 21, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28215965/menin-regulates-inhbb-expression-through-an-akt-ezh2-mediated-h3k27-histone-modification
#7
Samuele Gherardi, Doriane Ripoche, Ivan Mikaelian, Marie Chanal, Romain Teinturier, Delphine Goehrig, Martine Cordier-Bussat, Chang X Zhang, Ana Hennino, Philippe Bertolino
Although Men1 is a well-known tumour suppressor gene, little is known about the functions of Menin, the protein it encodes for. Since few years, numerous publications support a major role of Menin in the control of epigenetics gene regulation. While Menin interaction with MLL complex favours transcriptional activation of target genes through H3K4me3 marks, Menin also represses gene expression via mechanisms involving the Polycomb repressing complex (PRC). Interestingly, Ezh2, the PRC-methyltransferase that catalyses H3K27me3 repressive marks and Menin have been shown to co-occupy a large number of promoters...
February 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28214660/enhancer-of-zeste-homologue-2-plays-an-important-role-in-neuroblastoma-cell-survival-independent-of-its-histone-methyltransferase-activity
#8
Laurel T Bate-Eya, Hinco J Gierman, Marli E Ebus, Jan Koster, Huib N Caron, Rogier Versteeg, M Emmy M Dolman, Jan J Molenaar
Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed. We identified a neuroblastoma patient with a regional 7q36 gain, encompassing the enhancer of zeste homologue 2 (EZH2) gene. EZH2 is the histone methyltransferase of lysine 27 of histone H3 (H3K27me3) that forms the catalytic subunit of the polycomb repressive complex 2. H3K27me3 is commonly associated with the silencing of genes involved in cellular processes such as cell cycle regulation, cellular differentiation and cancer...
February 16, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28209718/demethylation-of-h3k27-is-essential-for-the-induction-of-direct-cardiac-reprogramming-by-mir-combo
#9
Sophie Dal-Pra, Conrad P Hodgkinson, Maria Mirotsou, Imke Kirste, Victor J Dzau
Rationale: Direct reprogramming of cardiac fibroblasts to cardac omyocytes has recently emerged as a novel and promising approach to regenerate the injured myocardium. We have previously demonstrated the feasibility of this approach in vitro and in vivo using a combination of four microRNAs (miR-1, miR-133, miR-208 and miR-499) that we named miR combo. However, the mechanism of miR combo mediated direct cardiac reprogramming is currently unknown. Objective: Here we investigated the possibility that miR combo initiated direct cardiac reprogramming through an epigenetic mechanism...
February 16, 2017: Circulation Research
https://www.readbyqxmd.com/read/28202673/molecular-architecture-of-polycomb-repressive-complexes
#10
REVIEW
Emily C Chittock, Sebastian Latwiel, Thomas C R Miller, Christoph W Müller
The polycomb group (PcG) proteins are a large and diverse family that epigenetically repress the transcription of key developmental genes. They form three broad groups of polycomb repressive complexes (PRCs) known as PRC1, PRC2 and Polycomb Repressive DeUBiquitinase, each of which modifies and/or remodels chromatin by distinct mechanisms that are tuned by having variable compositions of core and accessory subunits. Until recently, relatively little was known about how the various PcG proteins assemble to form the PRCs; however, studies by several groups have now allowed us to start piecing together the PcG puzzle...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28196760/polycomb-group-systems-in-fungi-new-models-for-understanding-polycomb-repressive-complex-2
#11
REVIEW
Zachary A Lewis
Polycomb group (PcG) proteins form multiple complexes that direct assembly of transcriptionally repressed chromatin, an essential process for multicellular development. Recent studies in plants and animals have uncovered surprising complexity in the form of multiple, variant PcG complexes governed by an extensive regulatory network. PcG proteins are absent from major yeast models, but recent research revealed minimal PcG systems in several well-studied fungi. In both animals and fungi, PcG complexes are responsive to local chromatin structure, but important aspects of PcG regulation remain unknown...
February 11, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28196077/enhancer-of-polycomb-coordinates-multiple-signaling-pathways-to-promote-both-cyst-and-germline-stem-cell-differentiation-in-the-drosophila-adult-testis
#12
Lijuan Feng, Zhen Shi, Xin Chen
Stem cells reside in a particular microenvironment known as a niche. The interaction between extrinsic cues originating from the niche and intrinsic factors in stem cells determines their identity and activity. Maintenance of stem cell identity and stem cell self-renewal are known to be controlled by chromatin factors. Herein, we use the Drosophila adult testis which has two adult stem cell lineages, the germline stem cell (GSC) lineage and the cyst stem cell (CySC) lineage, to study how chromatin factors regulate stem cell differentiation...
February 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28195122/integrated-genomic-analyses-of-de-novo-pathways-underlying-atypical-meningiomas
#13
Akdes Serin Harmancı, Mark W Youngblood, Victoria E Clark, Süleyman Coşkun, Octavian Henegariu, Daniel Duran, E Zeynep Erson-Omay, Leon D Kaulen, Tong Ihn Lee, Brian J Abraham, Matthias Simon, Boris Krischek, Marco Timmer, Roland Goldbrunner, S Bülent Omay, Jacob Baranoski, Burçin Baran, Geneive Carrión-Grant, Hanwen Bai, Ketu Mishra-Gorur, Johannes Schramm, Jennifer Moliterno, Alexander O Vortmeyer, Kaya Bilgüvar, Katsuhito Yasuno, Richard A Young, Murat Günel
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state...
February 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28194967/multicellular-tumor-spheroids-combined-with-mass-spectrometric-histone-analysis-to-evaluate-epigenetic-drugs
#14
Peter E Feist, Simone Sidoli, Xin Liu, Monica M Schroll, Sharif Rahmy, Rina Fujiwara, Benjamin A Garcia, Amanda B Hummon
Multicellular tumor spheroids (MCTS) are valuable in vitro tumor models frequently used to evaluate the penetration and efficacy of therapeutics. In this study, we evaluated potential differences in epigenetic markers, i.e., histone post-translational modifications (PTMs), in the layers of the HCT116 colon carcinoma MCTS. Cells were grown in agarose-coated 96 well plates, forming reproducible 1-mm-diameter MCTS. The MCTS were fractionated into three radially concentric portions, generating samples containing cells from the core, the mid and the external layers...
February 21, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28193854/gene-activation-of-smn-by-selective-disruption-of-lncrna-mediated-recruitment-of-prc2-for-the-treatment-of-spinal-muscular-atrophy
#15
Caroline J Woo, Verena K Maier, Roshni Davey, James Brennan, Guangde Li, John Brothers, Brian Schwartz, Susana Gordo, Anne Kasper, Trevor R Okamoto, Hans E Johansson, Berhan Mandefro, Dhruv Sareen, Peter Bialek, B Nelson Chau, Balkrishen Bhat, David Bullough, James Barsoum
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28192098/anti-leukemic-effects-of-hdaci-belinostat-and-hmti-3-deazaneplanocin-a-on-human-acute-promyelocytic-leukemia-cells
#16
Giedrė Valiulienė, Ieva Stirblytė, Monika Jasnauskaitė, Veronika Borutinskaitė, Rūta Navakauskienė
Development of acute myeloid leukemia is usually sustained by deregulated epigenome. Alterations in DNA methylation and histone modifications are common manifestations of the disease. Acute promyelocytic leukemia (APL) is not an exception. Therefore, drugs that target epigenetic processes suggest an appealing strategy for APL treatment. In this study we tested the anti-leukemic activity of histone deacetylase inhibitor (HDACi) Belinostat (PXD101, (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide), and histone methyltransferase inhibitor (HMTi) 3-Deazaneplanocin A (DZNep, 5R-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-cyclopentene-1S,2R-diol) combined with retinoic acid (RA) in APL cells NB4 and HL-60...
February 10, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28187462/recombinant-tat-bmi-1-fusion-protein-induces-ex-vivo-expansion-of-human-umbilical-cord-blood-derived-hematopoietic-stem-cells
#17
Bruna Codispoti, Nicola Rinaldo, Emanuela Chiarella, Michela Lupia, Cristina Barbara Spoleti, Maria Grazia Marafioti, Annamaria Aloisio, Stefania Scicchitano, Marco Giordano, Giovanna Nappo, Valeria Lucchino, Malcolm A S Moore, Pengbo Zhou, Maria Mesuraca, Heather Mandy Bond, Giovanni Morrone
Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28167697/prc2-is-dispensable-for-hotair-mediated-transcriptional-repression
#18
Manuela Portoso, Roberta Ragazzini, Živa Brenčič, Arianna Moiani, Audrey Michaud, Ivaylo Vassilev, Michel Wassef, Nicolas Servant, Bruno Sargueil, Raphaël Margueron
Long non-coding RNAs (lncRNAs) play diverse roles in physiological and pathological processes. Several lncRNAs have been suggested to modulate gene expression by guiding chromatin-modifying complexes to specific sites in the genome. However, besides the example of Xist, clear-cut evidence demonstrating this novel mode of regulation remains sparse. Here, we focus on HOTAIR, a lncRNA that is overexpressed in several tumor types and previously proposed to play a key role in gene silencing through direct recruitment of Polycomb Repressive Complex 2 (PRC2) to defined genomic loci...
February 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28165227/discovery-of-peptidomimetic-ligands-of-eed-as-allosteric-inhibitors-of-prc2
#19
Kimberly D Barnash, Juliana The, Jacqueline L Norris-Drouin, Stephanie H Cholensky, Beau M Worley, Fengling Li, Jacob I Stuckey, Peter J Brown, Masoud Vedadi, Cheryl H Arrowsmith, Stephen V Frye, Lindsey I James
The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein-protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED's recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression...
February 22, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28157505/polycomb-repressive-complex-1-generates-discrete-compacted-domains-that-change-during-differentiation
#20
Sharmistha Kundu, Fei Ji, Hongjae Sunwoo, Gaurav Jain, Jeannie T Lee, Ruslan I Sadreyev, Job Dekker, Robert E Kingston
Master regulatory genes require stable silencing by the polycomb group (PcG) to prevent misexpression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in ESCs and neural progenitors using 5C and super-resolution microscopy. The genomic loci of repressed PcG targets formed discrete, small (20-140 Kb) domains of tight interaction that corresponded to locations bound by canonical polycomb repressive complex 1 (PRC1)...
February 2, 2017: Molecular Cell
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