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histone methyltransferase

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https://www.readbyqxmd.com/read/28344658/flightless-i-governs-cell-fate-by-recruiting-the-sumo-isopeptidase-senp3-to-distinct-hox-genes
#1
Arnab Nayak, Anja Reck, Christian Morsczeck, Stefan Müller
BACKGROUND: Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinct HOX genes, including the osteogenic master regulator DLX3. A comprehensive mechanism that regulates SENP3 transcriptional function was not understood. RESULTS: Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28338320/inhibitors-of-protein-methyltransferases-and-demethylases
#2
H Ümit Kaniskan, Michael L Martini, Jian Jin
Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets...
March 24, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28338204/nsd2-promotes-osteosarcoma-cell-proliferation-and-metastasis-by-inhibiting-e-cadherin-expression
#3
M-H Lu, M-F Fan, X-D Yu
OBJECTIVE: Osteosarcoma is one of the most common malignant bone tumors. The mechanisms of osteosarcoma development and invasion have been studied for periods of time, yet targeted therapy for improving survival has not been well established. Histone lysine methyltransferase NSD2 was frequently overexpressed in multiple types of cancer such as multiple myeloma, stomach and colon cancer, and the overexpression of it usually associated with aggressiveness tumor type. However, the expression status and function of NSD2 are still ambiguous in osteosarcoma...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28337327/discovery-of-potent-selective-and-structurally-novel-dot1l-inhibitors-by-a-fragment-linking-approach
#4
Henrik Möbitz, Rainer Machauer, Philipp Holzer, Andrea Vaupel, Frédéric Stauffer, Christian Ragot, Giorgio Caravatti, Clemens Scheufler, Cesar Fernandez, Ulrich Hommel, Ralph Tiedt, Kim S Beyer, Chao Chen, Hugh Zhu, Christoph Gaul
Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28336670/pi3k-pathway-regulates-er-dependent-transcription-in-breast-cancer-through-the-epigenetic-regulator-kmt2d
#5
Eneda Toska, Hatice U Osmanbeyoglu, Pau Castel, Carmen Chan, Ronald C Hendrickson, Moshe Elkabets, Maura N Dickler, Maurizio Scaltriti, Christina S Leslie, Scott A Armstrong, José Baselga
Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples...
March 24, 2017: Science
https://www.readbyqxmd.com/read/28332284/ezh2-mediated-repression-of-dkk1-promotes-hepatic-stellate-cell-activation-and-hepatic-fibrosis
#6
Yang Yang, Xiao-Xia Chen, Wan-Xia Li, Xiao-Qin Wu, Cheng Huang, Juan Xie, Yu-Xin Zhao, Xiao-Ming Meng, Jun Li
EZH2, a histone H3 lysine-27-specific methyltransferase, is involved in diverse physiological and pathological processes including cell proliferation and differentiation. However, the role of EZH2 in liver fibrosis is largely unknown. In this study, it was identified that EZH2 promoted Wnt pathway-stimulated fibroblasts in vitro and in vivo by repressing Dkk-1, which is a Wnt pathway antagonist. The expression of EZH2 was increased in CCl4 -induced rat liver and primary HSCs as well as TGF-β1-treated HSC-T6, whereas the expression of Dkk1 was reduced...
March 23, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28330868/protein-arginine-methyltransferase-1-modulates-innate-immune-responses-through-regulation-of-peroxisome-proliferator-activated-receptor-gamma-dependent-macrophage-differentiation
#7
Irina Tikhanovich, Jie Zhao, Jody Olson, Abby Adams, Ryan Taylor, Brian Bridges, Laurie Marshall, Benjamin Roberts, Steven A Weinman
Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in Protein Arginine Methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses in vivo, we created a cell type specific knockout mouse model. We showed that myeloid specific PRMT1 knockout mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture...
March 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28327608/kdm4b-histone-demethylase-and-g9a-regulate-expression-of-vascular-adhesion-proteins-in-cerebral-microvessels
#8
Ji-Young Choi, Sang-Sun Yoon, Sang-Eun Kim, Sangmee Ahn Jo
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28323035/naturally-occurring-anti-cancer-agents-targeting-ezh2
#9
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/28320505/fine-tuning-of-gene-expression-dynamics-by-the-set2-rpd3s-pathway
#10
Bo Bae Lee, Ji Hyun Kim, TaeSoo Kim
RNA polymerase II-interacting the Set2 methyltransferase co-transcriptionally methylates histone H3 at lysine 36 within the body of genes. This modification facilitates histone deacetylation by Rpd3S HDAC in 3' transcribed regions to suppress cryptic initiation and slow elongation. Although this pathway is important for global deacetylation, no strong effects on genome-wide transcription have been seen under optimized laboratory conditions. In contrast, this pathway slows the kinetics of mRNA induction when target genes are induced upon environmental changes...
March 21, 2017: BMB Reports
https://www.readbyqxmd.com/read/28319045/akt-mediated-stabilization-of-histone-methyltransferase-whsc1-promotes-prostate-cancer-metastasis
#11
Ni Li, Wei Xue, Huairui Yuan, Baijun Dong, Yufeng Ding, Yongfeng Liu, Min Jiang, Shan Kan, Tongyu Sun, Jiale Ren, Qiang Pan, Xiang Li, Peiyuan Zhang, Guohong Hu, Yan Wang, Xiaoming Wang, Qintong Li, Jun Qin
Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28315782/human-comt-over-expression-confers-a-heightened-susceptibility-to-dyskinesia-in-mice
#12
Oscar Solís, Jose-Rubén García-Montes, Patricia Garcia-Sanz, Antonio S Herranz, Maria-José Asensio, Gina Kang, Noboru Hiroi, Rosario Moratalla
Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor l-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor behaviors and molecular alterations in a mouse model of dyskinesia. Transgenic mice overexpressing human COMT (TG) and their wildtype (WT) littermates received unilateral 6-OHDA lesions in the dorsal striatum and were treated chronically with l-DOPA for two weeks. l-DOPA-induced dyskinesia was exacerbated in TG mice without altering l-DOPA motor efficacy as determined by contralateral rotations or motor coordination...
March 16, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28315733/wt1-ameliorates-podocyte-injury-via-repression-of-ezh2-%C3%AE-catenin-pathway-in-diabetic-nephropathy
#13
Jiao Wan, Xiaoyan Hou, Zhanmei Zhou, Jian Geng, Jianwei Tian, Jing Nie, Xiaoyan Bai
Epigenetic modulation of podocyte injury plays a pivotal role in diabetic nephropathy (DN). Wilm's tumor 1 (WT1) has been found to have opposing roles with β-catenin in podocyte biology. Herein, we asked whether the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) promotes WT1-induced podocyte injury via β-catenin activation and the underlying mechanisms. We found that WT1 antagonized EZH2 and ameliorated β-catenin-mediated podocyte injury as demonstrated by attenuated podocyte mesenchymal transition, maintenance of podocyte architectural integrity, decreased podocyte apoptosis and oxidative stress...
March 15, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28314309/elevated-metabolic-activity-on-18-f-fdg-pet-ct-is-associated-with-the-expression-of-ezh2-in-non-small-cell-lung-cancer
#14
Gouji Toyokawa, Kazuki Takada, Tatsuro Okamoto, Yuka Kozuma, Taichi Matsubara, Naoki Haratake, Takaki Akamine, Shinkichi Takamori, Masakazu Katsura, Fumihiro Shoji, Ryuji Hamamoto, Yoshinao Oda, Yoshihiko Maehara
BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in the pathogenesis of lung cancer. We evaluated the metabolic characteristics of non-small cell lung cancer (NSCLC) in patients with and without expression of EZH2 using (18)F-fluorodeoxyglucose positron-emission tomography/ computed tomography ((18)F-FDG PET/CT). MATERIALS AND METHODS: The EZH2 protein expression of 268 patients with resected NSCLC, whose preoperative (18)F-FDG PET/CT information was available, was evaluated by immunohistochemistry with clone 6A10 antibody; cases with Allred score ≥3 were considered positive...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28306504/targeting-of-polycomb-repressive-complex-2-to-rna-by-short-repeats-of-consecutive-guanines
#15
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/28301528/genome-wide-mapping-of-histone-h3k9me2-in-acute-myeloid-leukemia-reveals-large-chromosomal-domains-associated-with-massive-gene-silencing-and-sites-of-genome-instability
#16
Anna C Salzberg, Abigail Harris-Becker, Evgenya Y Popova, Nikki Keasey, Thomas P Loughran, David F Claxton, Sergei A Grigoryev
A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562...
2017: PloS One
https://www.readbyqxmd.com/read/28300471/decoupling-of-dna-methylation-and-activity-of-intergenic-line-1-promoters-in-colorectal-cancer
#17
Natasha Vafadar-Isfahani, Christina Parr, Lara E McMillan, Juliane Sanner, Zhao Yeo, Stephen Saddington, Oliver Peacock, Hazel A Cruickshanks, Richard R Meehan, Jonathan N Lund, Cristina Tufarelli
Hypomethylation of LINE-1 repeats in cancer has been proposed as the main mechanism behind their activation; this assumption, however, was based on findings from early studies that were biased towards young and transpositionally active elements. Here, we investigate the relationship between methylation of two intergenic, transpositionally inactive LINE-1 elements and expression of the LINE-1 chimeric transcript (LCT) 13 and LCT14 driven by their antisense promoters (L1-ASP). Our data from DNA modification, expression, and 5'RACE analyses suggest that colorectal cancer methylation in the regions analyzed is not always associated with LCT repression...
March 16, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28294943/a-team-of-heterochromatin-factors-collaborates-with-small-rna-pathways-to-combat-repetitive-elements-and-germline-stress
#18
Alicia N McMurchy, Przemyslaw Stempor, Tessa Gaarenstroom, Brian Wysolmerski, Yan Dong, Darya Aussianikava, Alex Appert, Ni Huang, Paulina Kolasinska-Zwierz, Alexandra Sapetschnig, Eric A Miska, Julie Ahringer
Repetitive sequences derived from transposons make up a large fraction of eukaryotic genomes and must be silenced to protect genome integrity. Repetitive elements are often found in heterochromatin; however, the roles and interactions of heterochromatin proteins in repeat regulation are poorly understood. Here we show that a diverse set of C. elegans heterochromatin proteins act together with the piRNA and nuclear RNAi pathways to silence repetitive elements and prevent genotoxic stress in the germ line. Mutants in genes encoding HPL-2/HP1, LIN-13, LIN-61, LET-418/Mi-2, and H3K9me2 histone methyltransferase MET-2/SETDB1 also show functionally redundant sterility, increased germline apoptosis, DNA repair defects, and interactions with small RNA pathways...
March 15, 2017: ELife
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
#19
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/28290609/senescence-of-mesenchymal-stem-cells-review
#20
Yi Li, Qiong Wu, Yujia Wang, Li Li, Hong Bu, Ji Bao
Mesenchymal stem cells (MSCs) have been used in cell-based therapy for various diseases, due to their immunomodulatory and inflammatory effects. However, the function of MSCs is known to decline with age, a process that is called senescence. To date, the process of MSC senescence remains unknown as in-depth understanding of the mechanisms involved in cellular senescence is lacking. First, senescent MSCs are so heterogeneous that not all of them express the same phenotypic markers. In addition, the genes and signaling pathways which regulate this process in MSCs are still unknown...
March 9, 2017: International Journal of Molecular Medicine
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