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https://www.readbyqxmd.com/read/28346433/a-cytosolic-ezh1-isoform-modulates-a-prc2-ezh1-epigenetic-adaptive-response-in-postmitotic-cells
#1
Beatrice Bodega, Federica Marasca, Valeria Ranzani, Alessandro Cherubini, Francesco Della Valle, Maria Victoria Neguembor, Michel Wassef, Alessio Zippo, Chiara Lanzuolo, Massimiliano Pagani, Valerio Orlando
The evolution of chromatin-based epigenetic cell memory may be driven not only by the necessity for cells to stably maintain transcription programs, but also by the need to recognize signals and allow plastic responses to environmental stimuli. The mechanistic role of the epigenome in adult postmitotic tissues, however, remains largely unknown. In vertebrates, two variants of the Polycomb repressive complex (PRC2-Ezh2 and PRC2-Ezh1) control gene silencing via methylation of histone H3 on Lys27 (H3K27me). Here we describe a reversible mechanism that involves a novel isoform of Ezh1 (Ezh1β)...
March 27, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28342717/slow-chromatin-dynamics-allow-polycomb-target-genes-to-filter-fluctuations-in-transcription-factor-activity
#2
Scott Berry, Caroline Dean, Martin Howard
Genes targeted by Polycomb repressive complex 2 (PRC2) are regulated in cis by chromatin modifications and also in trans by diffusible regulators such as transcription factors. Here, we introduce a mathematical model in which transcription directly antagonizes Polycomb silencing, thereby linking these cis- and trans-regulatory inputs to gene expression. The model is parameterized by recent experimental data showing that PRC2-mediated repressive chromatin modifications accumulate extremely slowly. The model generates self-perpetuating, bistable active and repressed chromatin states that persist through DNA replication, thereby ensuring high-fidelity transmission of the current chromatin state...
March 21, 2017: Cell Systems
https://www.readbyqxmd.com/read/28340355/the-human-immunodeficiency-virus-1-asp-rna-promotes-viral-latency-by-recruiting-the-polycomb-repressor-complex-2-and-promoting-nucleosome-assembly
#3
Juan C Zapata, Federica Campilongo, Robert A Barclay, Catherine DeMarino, Maria D Iglesias-Ussel, Fatah Kashanchi, Fabio Romerio
Various epigenetic marks at the HIV-1 5'LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3'LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells...
March 21, 2017: Virology
https://www.readbyqxmd.com/read/28323035/naturally-occurring-anti-cancer-agents-targeting-ezh2
#4
Fahimeh Shahabipour, Michele Caraglia, Muhammed Majeed, Giuseppe Derosa, Pamela Maffioli, Amirhossein Sahebkar
Natural products are considered as promising tools for the prevention and treatment of cancer. The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase unit of polycomb repressor complexes such as PRC2 complex that has oncogenic roles through interference with growth and metastatic potential. Several agents targeting EZH2 has been discovered but they often induce side effects in clinical trials. Recently, EZH2 has emerged as a potential target of natural products with documented anti-cancer effects and this discloses a new scenario for the development of EZH2 inhibitory strategies with agents with low cytotoxic detrimental effects...
March 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28322158/effect-and-mechanism-of-curcumin-on-ezh2-mir-101-regulatory-feedback-loop-in-multiple-myeloma
#5
Chuanqing Wu, Tuo Ruan, Weizhen Liu, Xiaojie Zhu, Juan Pan, Wen Lu, Chen Yan, Kaixiong Tao, Weikang Zhang, Chun Zhang
BACKGROUND: Multiple myeloma is the second most prevalent hematologic malignancy and thought to be incurable. Therefore, it's urgent to find new drugs for treatment. Some experiments have shown that curcumin might have great potential in treating multiple myeloma, while the mechanism is still unknown. EZH2 and SUZ12 are the core proteins in PRC2 and their expression are increased in various human cancers, including the poor prognostic multiple myeloma. Meanwhile, the regulation of miRNAs and EZH2 has been demonstrated in other cancer researches, like lung cancer, pancreatic cancer, leukemia and so on...
March 17, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28320776/epigenomic-promoter-alterations-amplify-gene-isoform-and-immunogenic-diversity-in-gastric-adenocarcinoma
#6
Aditi Qamra, Manjie Xing, Nisha Padmanabhan, Jeffrey Jun Ting Kwok, Shenli Zhang, Xu Chang, Yan Shan Leong, Ai Ping Lee Lim, Qianqao Tang, WenFong Ooi, Joyce Suling Lin, Tannistha Nandi, Xiaosai Yao, Xuewen Ong, Minghui Lee, Su Ting Tay, Angie Tan Lay Keng, Erna Gondo Santoso, Cedric Chuan Young Ng, Alvin Ng, Apinya Jusakul, Duane Smoot, Hassan Ashktorab, Sun Young Rha, Khay Guan Yeoh, Wei Peng Yong, Pierce K H Chow, Weng Hoong Chan, Hock Soo Ong, Khee Chee Soo, Kyoung-Mee Kim, Wai Keong Wong, Steven G Rozen, Bin Tean Teh, Dennis Kappei, Jeeyun Lee, John Connolly, Patrick Tan
Promoter elements play important roles in isoform and cell-type specific expression. We surveyed the epigenomic promoter landscape of gastric adenocarcinoma (GC), analyzing 110 chromatin profiles (H3K4me3, H3K4me1, H3K27ac) of primary GCs, GC lines, and non-malignant gastric tissues. We identified ~2000 promoter alterations (somatic promoters), many deregulated in various epithelial malignancies and mapping frequently to alternative promoters within the same gene, generating potential pro-oncogenic isoforms (RASA3)...
March 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28320739/a-covalently-bound-inhibitor-triggers-ezh2-degradation-through-chip-mediated-ubiquitination
#7
Xu Wang, Wei Cao, Jianjun Zhang, Ming Yan, Qin Xu, Xiangbing Wu, Lixin Wan, Zhiyuan Zhang, Chenping Zhang, Xing Qin, Meng Xiao, Dongxia Ye, Yuyang Liu, Zeguang Han, Shaomeng Wang, Li Mao, Wenyi Wei, Wantao Chen
Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2- and methyltransferase-independent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2-targeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2-SET domain, triggering EZH2 degradation through COOH terminus of Hsp70-interacting protein (CHIP)-mediated ubiquitination...
March 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28306504/targeting-of-polycomb-repressive-complex-2-to-rna-by-short-repeats-of-consecutive-guanines
#8
Xueyin Wang, Karen J Goodrich, Anne R Gooding, Haroon Naeem, Stuart Archer, Richard D Paucek, Daniel T Youmans, Thomas R Cech, Chen Davidovich
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that trimethylates H3K27, a mark of repressed chromatin. Mammalian PRC2 binds RNA promiscuously, with thousands of target transcripts in vivo. But what does PRC2 recognize in these RNAs? Here we show that purified human PRC2 recognizes G > C,U ≫ A in single-stranded RNA and has a high affinity for folded guanine quadruplex (G4) structures but little binding to duplex RNAs. Importantly, G-tract motifs are significantly enriched among PRC2-binding transcripts in vivo...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28302792/propagation-of-polycomb-repressed-chromatin-requires-sequence-specific-recruitment-to-dna
#9
Friederike Laprell, Katja Finkl, Jürg Müller
Epigenetic inheritance models posit that during Polycomb repression, Polycomb Repressive Complex 2 (PRC2) propagates histone H3K27 tri-methylation (H3K27me3) independently of DNA sequence. We show that insertion of Polycomb Response Element (PRE) DNA into the Drosophila genome creates extended domains of H3K27me3-modified nucleosomes in the flanking chromatin and causes repression of a linked reporter gene. After excision of PRE DNA, H3K27me3 nucleosomes become diluted with each round of DNA replication and reporter gene repression is lost, whereas in replication-stalled cells, H3K27me3 levels stay high and repression persists...
March 16, 2017: Science
https://www.readbyqxmd.com/read/28295484/who-2016-classification-changes-and-advancements-in-the-diagnosis-of-miscellaneous-primary-cns-tumours
#10
Felix Sahm, David E Reuss, Caterina Giannini
This short review highlights significant changes and recent findings incorporated to varying extent in the WHO 2016 definition of a variety of tumours, including peripheral nerve sheath tumours, meningiomas, mesenchymal non-meningothelial tumours, melanocytic tumours, lymphomas and histiocytic tumours, germ cell tumours and non-neuroendocrine pituitary tumours. Most notable classification changes include: adding "hybrid nerve sheath tumours" to the spectrum of benign nerve sheath tumours; an updated definition of atypical meningioma (WHO grade II), including cases with brain invasion; recognizing dural solitary fibrous tumour (SFT) and haemangiopericytoma (HPC) as a single tumour entity characterized by NAB2 and STAT6 gene fusions for which the term solitary SFT/HPC was chosen; recognizing that pituitary granular cell tumour, spindle cell oncocytoma, and pituicytoma all share nuclear expression of TTF-1, possibly representing a spectrum of a single nosological entity derived from posterior pituitary glial cells...
March 12, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28292935/selective-killing-of-smarca2-and-smarca4-deficient-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-cells-by-inhibition-of-ezh2-in-vitro-and-in-vivo-preclinical-models
#11
Elayne Chan-Penebre, Kelli Armstrong, Allison Drew, Alexandra R Grassian, Igor Feldman, Sarah K Knutson, Kristy Kuplast-Barr, Maria Roche, John Campbell, Peter Ho, Robert A Copeland, Richard Chesworth, Jesse J Smith, Heike Keilhack, Scott A Ribich
The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28285903/prc2-facilitates-the-regulatory-topology-required-for-poised-enhancer-function-during-pluripotent-stem-cell-differentiation
#12
Sara Cruz-Molina, Patricia Respuela, Christina Tebartz, Petros Kolovos, Milos Nikolic, Raquel Fueyo, Wilfred F J van Ijcken, Frank Grosveld, Peter Frommolt, Hisham Bazzi, Alvaro Rada-Iglesias
Poised enhancers marked by H3K27me3 in pluripotent stem cells have been implicated in the establishment of somatic expression programs during embryonic stem cell (ESC) differentiation. However, the functional relevance and mechanism of action of poised enhancers remain unknown. Using CRISPR/Cas9 technology to engineer precise genetic deletions, we demonstrate that poised enhancers are necessary for the induction of major anterior neural regulators. Interestingly, circularized chromosome conformation capture sequencing (4C-seq) shows that poised enhancers already establish physical interactions with their target genes in ESCs in a polycomb repressive complex 2 (PRC2)-dependent manner...
February 28, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28283507/inhibition-of-ezh2-or-bet-suppresses-diffuse-intrinsic-pontine-glioma
#13
(no author information available yet)
H3K27M-expressing diffuse intrinsic pontine gliomas (DIPG) are dependent on residual PRC2 activity.
March 10, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28281550/reduced-h3k27me3-expression-in-merkel-cell-polyoma-virus-positive-tumors
#14
Klaus J Busam, Melissa P Pulitzer, Daniel C Coit, Maria Arcila, Danielle Leng, Achim A Jungbluth, Thomas Wiesner
Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation)...
March 10, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28263309/ezh2-is-a-potential-therapeutic-target-for-h3k27m-mutant-pediatric-gliomas
#15
Faizaan Mohammad, Simon Weissmann, Benjamin Leblanc, Deo P Pandey, Jonas W Højfeldt, Itys Comet, Chunqin Zheng, Jens Vilstrup Johansen, Nicolas Rapin, Bo T Porse, Andrey Tvardovskiy, Ole N Jensen, Nagore G Olaciregui, Cinzia Lavarino, Mariona Suñol, Carmen de Torres, Jaume Mora, Angel M Carcaboso, Kristian Helin
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3...
February 27, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28263307/therapeutic-targeting-of-polycomb-and-bet-bromodomain-proteins-in-diffuse-intrinsic-pontine-gliomas
#16
Andrea Piunti, Rintaro Hashizume, Marc A Morgan, Elizabeth T Bartom, Craig M Horbinski, Stacy A Marshall, Emily J Rendleman, Quanhong Ma, Yoh-Hei Takahashi, Ashley R Woodfin, Alexander V Misharin, Nebiyu A Abshiru, Rishi R Lulla, Amanda M Saratsis, Neil L Kelleher, C David James, Ali Shilatifard
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis...
February 27, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28256832/allosteric-inactivation-of-polycomb-repressive-complex-2-prc2-by-inhibiting-its-adapter-protein-embryonic-ectodomain-development-eed
#17
Chao-Yie Yang, Shaomeng Wang
Aberrant PRC2 activity produces gene repressive epigenetic marks in multiple diseases and led to identification of Ezh2 as a drug target. Recent studies have shown that the epigenetic reader protein EED, associated with Ezh2 in PRC2, has an additional function to stimulate the PRC2 activity after binding to H3K27me3. Optimizing a compound known to block the H3K27me3 site in EED discovered by in-house screening, Novartis scientists have now produced a compound that shows durable tumor regression in a lymphoma xenograft model...
March 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28254491/ezh1-in-germ-cells-safeguards-the-function-of-prc2-during-spermatogenesis
#18
Weipeng Mu, Joshua Starmer, Yoichiro Shibata, Della Yee, Terry Magnuson
We previously reported the requirement of Polycomb Repressive Complex 2 (PRC2) for spermatogenesis through transcriptional repression of somatic genes and meiosis-specific genes. To characterize how PRC2's two methyltransferase subunits, EZH1 and EZH2, regulate histone H3 lysine 27 (H3K27) methylation during germ cell development, we generated mouse models with a germline ablation of EZH1 and/or EHZ2. Only the combined loss of EZH1 and EZH2 caused a depletion of global H3K27me3 marks and meiotic arrest in spermatocytes...
February 27, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28254486/sar-of-amino-pyrrolidines-as-potent-and-novel-protein-protein-interaction-inhibitors-of-the-prc2-complex-through-eed-binding
#19
Michael L Curtin, Marina A Pliushchev, Huan-Qiu Li, Maricel Torrent, Justin D Dietrich, Clarissa G Jakob, Haizhong Zhu, Hongyu Zhao, Ying Wang, Zhiqin Ji, Richard F Clark, Kathy A Sarris, Sujatha Selvaraju, Bailin Shaw, Mikkel A Algire, Yupeng He, Paul L Richardson, Ramzi F Sweis, Chaohong Sun, Gary G Chiang, Michael R Michaelides
Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28246360/multiple-histone-lysine-methyltransferases-are-required-for-the-establishment-and-maintenance-of-hiv-1-latency
#20
Kien Nguyen, Biswajit Das, Curtis Dobrowolski, Jonathan Karn
We showed previously that the histone lysine methyltransferase (HKMT) H3K27me3 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2) and is required for the maintenance of HIV-1 latency in Jurkat T cells. Here we show, by using chromatin immunoprecipitation experiments, that both PRC2 and euchromatic histone-lysine N-methyltransferase 2 (EHMT2), the G9a H3K9me2-3 methyltransferase, are highly enriched at the proviral 5' long terminal repeat (LTR) and rapidly displaced upon proviral reactivation...
February 28, 2017: MBio
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