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H3K27me3

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https://www.readbyqxmd.com/read/28092155/discovery-of-first-in-class-potent-and-orally-bioavailable-eed-inhibitor-with-robust-anti-cancer-efficacy
#1
Ying Huang, Jeff Zhang, Zhengtian Yu, Hailong Zhang, Youzhen Wang, Andreas Lingel, Wei Qi, X Justin Gu, Kehao Zhao, Michael David Shultz, Long Wang, Xingnian Fu, Yongfeng Sun, Qiong Zhang, Xiangqing Jiang, Jiang-Wei Zhang, Chunye Zhang, Ling Li, Jue Zeng, Lijian Feng, Chao Zhang, Yueqin Liu, Man Zhang, Lijun Zhang, Mengxi Zhao, Zhenting Gao, Xianghui Liu, Douglas Fang, Haibing Guo, Yuan Mi, Tobias Gabriel, Michael P Dillon, Peter Atadja, Counde Oyang
Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit Polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (Tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective and orally bioavailable EED inhibitor EED226 (compound 43)...
January 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28091603/repo-man-pp1-regulates-heterochromatin-formation-in-interphase
#2
Inês J de Castro, James Budzak, Maria L Di Giacinto, Lorena Ligammari, Ezgi Gokhan, Christos Spanos, Daniela Moralli, Christine Richardson, Jose I de Las Heras, Silvia Salatino, Eric C Schirmer, Katharine S Ullman, Wendy A Bickmore, Catherine Green, Juri Rappsilber, Sarah Lamble, Martin W Goldberg, Veronica Vinciotti, Paola Vagnarelli
Repo-Man is a protein phosphatase 1 (PP1) targeting subunit that regulates mitotic progression and chromatin remodelling. After mitosis, Repo-Man/PP1 remains associated with chromatin but its function in interphase is not known. Here we show that Repo-Man, via Nup153, is enriched on condensed chromatin at the nuclear periphery and at the edge of the nucleopore basket. Repo-Man/PP1 regulates the formation of heterochromatin, dephosphorylates H3S28 and it is necessary and sufficient for heterochromatin protein 1 binding and H3K27me3 recruitment...
January 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28077316/chromatin-dynamics-regulate-mesenchymal-stem-cell-lineage-specification-and-differentiation-to-osteogenesis
#3
Hai Wu, Jonathan A R Gordon, Troy W Whitfield, Phillip W L Tai, Andre J van Wijnen, Janet L Stein, Gary S Stein, Jane B Lian
Multipotent mesenchymal stromal cells (MSCs) are critical for regeneration of multiple tissues. Epigenetic mechanisms are fundamental regulators of lineage specification and cell fate, and as such, we addressed the question of which epigenetic modifications characterize the transition of nascent MSCs to a tissue specific MSC-derived phenotype. By profiling the temporal changes of seven histone marks correlated to gene expression during proliferation, early commitment, matrix deposition, and mineralization stages, we identified distinct epigenetic mechanisms that regulate transcriptional programs necessary for tissue-specific phenotype development...
January 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28072869/discovery-and-molecular-basis-of-a-diverse-set-of-polycomb-repressive-complex-2-inhibitors-recognition-by-eed
#4
Ling Li, Hailong Zhang, Man Zhang, Mengxi Zhao, Lijian Feng, Xiao Luo, Zhenting Gao, Ying Huang, Ophelia Ardayfio, Ji-Hu Zhang, Ying Lin, Hong Fan, Yuan Mi, Guobin Li, Lei Liu, Leying Feng, Fangjun Luo, Lin Teng, Wei Qi, Johannes Ottl, Andreas Lingel, Dirksen E Bussiere, Zhengtian Yu, Peter Atadja, Chris Lu, En Li, Justin Gu, Kehao Zhao
Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model...
2017: PloS One
https://www.readbyqxmd.com/read/28055238/valproic-acid-increases-histone-acetylation-and-alters-gene-expression-in-the-donor-cells-but-does-not-improve-the-in-vitro-developmental-competence-of-buffalo-bubalus-bubalis-embryos-produced-by-hand-made-cloning
#5
Naresh L Selokar, Monika Saini, Himanshu Agrawal, Prabhat Palta, Manmohan Singh Chauhan, Radheysham Manik, Suresh Kumar Singla
Use of histone deacetylase inhibitors (HDACis) is believed to improve the developmental competence and quality of cloned embryos produced. We examined the effects of treatment of buffalo fibroblasts with valproic acid (VPA), a HDACi on these cells and on embryos produced from them by hand-made cloning. VPA treatment (1.5, 3.0, or 4.5 mM) altered (p < 0.05) the growth characteristics and relative expression level of HDAC1, DNMT1, DNMT3a, P53, and CASPASE3, and the global level of H3K9/14ac, H4K5ac, and H3K18ac but not H3K27me3 in the cells...
January 5, 2017: Cellular Reprogramming
https://www.readbyqxmd.com/read/28052258/roles-of-h3k27me2-and-h3k27me3-examined-during-fate-specification-of-embryonic-stem-cells
#6
Aster H Juan, Stan Wang, Kyung Dae Ko, Hossein Zare, Pei-Fang Tsai, Xuesong Feng, Karinna O Vivanco, Anthony M Ascoli, Gustavo Gutierrez-Cruz, Jordan Krebs, Simone Sidoli, Adam L Knight, Roger A Pedersen, Benjamin A Garcia, Rafael Casellas, Jizhong Zou, Vittorio Sartorelli
No abstract text is available yet for this article.
January 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28052011/ezh2-inhibition-in-multiple-myeloma-downregulates-myeloma-associated-oncogenes-and-upregulates-micrornas-with-potential-tumor-suppressor-functions
#7
Mohammad Alzrigat, Alba Atienza Párraga, Prasoon Agarwal, Hadil Zureigat, Anders Österborg, Hareth Nahi, Anqi Ma, Jian Jin, Kenneth Nilsson, Fredrik Öberg, Antonia Kalushkova, Helena Jernberg-Wiklund
Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM...
December 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/28045091/ctcf-interacts-with-the-lytic-hsv-1-genome-to-promote-viral-transcription
#8
Fengchao Lang, Xin Li, Olga Vladimirova, Benxia Hu, Guijun Chen, Yu Xiao, Vikrant Singh, Danfeng Lu, Lihong Li, Hongbo Han, J M A S P Wickramasinghe, Sheryl T Smith, Chunfu Zheng, Qihan Li, Paul M Lieberman, Nigel W Fraser, Jumin Zhou
CTCF is an essential chromatin regulator implicated in important nuclear processes including in nuclear organization and transcription. Herpes Simplex Virus-1 (HSV-1) is a ubiquitous human pathogen, which enters productive infection in human epithelial and many other cell types. CTCF is known to bind several sites in the HSV-1 genome during latency and reactivation, but its function has not been defined. Here, we report that CTCF interacts extensively with the HSV-1 DNA during lytic infection by ChIP-seq, and its knockdown results in the reduction of viral transcription, viral genome copy number and virus yield...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28042859/a-novel-role-of-silibinin-as-a-putative-epigenetic-modulator-in-human-prostate-carcinoma
#9
Ioannis Anestopoulos, Aristeidis P Sfakianos, Rodrigo Franco, Katerina Chlichlia, Mihalis I Panayiotidis, David J Kroll, Aglaia Pappa
Silibinin, extracted from milk thistle (Silybum marianum L.), has exhibited considerable preclinical activity against prostate carcinoma. Its antitumor and chemopreventive activities have been associated with diverse effects on cell cycle, apoptosis, and receptor-dependent mitogenic signaling pathways. Here we hypothesized that silibinin's pleiotropic effects may reflect its interference with epigenetic mechanisms in human prostate cancer cells. More specifically, we have demonstrated that silibinin reduces gene expression levels of the Polycomb Repressive Complex 2 (PRC2) members Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste Homolog 12 (SUZ12), and Embryonic Ectoderm Development (EED) in DU145 and PC3 human prostate cancer cells, as evidenced by Real Time Polymerase Chain Reaction (RT-PCR)...
December 31, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28034954/a-flowering-locus-c-homolog-is-a-vernalization-regulated-repressor-in-brachypodium-and-is-cold-regulated-in-wheat
#10
Neha Sharma, Philip Ruelens, Mariella Dhauw, Thomas Maggen, Niklas Dochy, Sanne Torfs, Kerstin Kaufmann, Antje Rohde, Koen Geuten
Winter cereals require prolonged cold to transition from vegetative to reproductive development. This process, referred to as vernalization, has been extensively studied in Arabidopsis thaliana. In Arabidopsis, a key flowering repressor called FLOWERING LOCUS C (FLC) quantitatively controls the vernalization requirement. By contrast, in cereals, the vernalization response is mainly regulated by the VERNALIZATION genes, VRN1 and VRN2. Here we characterize ODDSOC2, a recently identified FLC ortholog in monocots, for the first time knowing that it belongs to the FLC lineage...
December 29, 2016: Plant Physiology
https://www.readbyqxmd.com/read/28031467/maternal-sall4-is-indispensable-for-epigenetic-maturation-of-mouse-oocytes
#11
Kai Xu, Xia Chen, Hui Yang, Yiwen Xu, Yuanlin He, Chenfei Wang, Hua Huang, Baodong Liu, Wenqiang Liu, Jingyi Li, Xiaochen Kou, Yanhong Zhao, Kun Zhao, Linfeng Zhang, Zhenzhen Hou, Hong Wang, Hailin Wang, Jing Li, Hengyu Fan, Fengchao Wang, Yawei Gao, Yong Zhang, Jiayu Chen, Shaorong Gao
Splat-like 4 (Sall4) plays important roles in maintaining pluripotency of embryonic stem cells and in various developmental processes. Here, we find that Sall4 is highly expressed in oocytes and early embryos. To investigate the roles of SALL4 in oogenesis, we generated Sall4 maternal specific knockout mice by using CRISPR/Cas9 system. And we find that the maternal deletion of Sall4 causes developmental arrest of oocytes at germinal vesicle stage with non-surrounded nucleus and the subsequent meiosis resumption is prohibited...
December 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28024297/variable-chromatin-structure-revealed-by-in-situ-spatially-correlated-dna-cleavage-mapping
#12
Viviana I Risca, Sarah K Denny, Aaron F Straight, William J Greenleaf
Chromatin structure at the length scale encompassing local nucleosome-nucleosome interactions is thought to play a crucial role in regulating transcription and access to DNA. However, this secondary structure of chromatin remains poorly understood compared with the primary structure of single nucleosomes or the tertiary structure of long-range looping interactions. Here we report the first genome-wide map of chromatin conformation in human cells at the 1-3 nucleosome (50-500 bp) scale, obtained using ionizing radiation-induced spatially correlated cleavage of DNA with sequencing (RICC-seq) to identify DNA-DNA contacts that are spatially proximal...
December 26, 2016: Nature
https://www.readbyqxmd.com/read/28007739/ischemic-preconditioning-confers-epigenetic-repression-of-mtor-and-induction-of-autophagy-through-g9a-dependent-h3k9-dimethylation
#13
Olof Gidlöf, Andrea L Johnstone, Kerstin Bader, Bohdan B Khomtchouk, Jiaqi J O'Reilly, Selvi Celik, Derek J Van Booven, Claes Wahlestedt, Bernhard Metzler, David Erlinge
BACKGROUND: Ischemic preconditioning (IPC) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post-translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning. METHODS AND RESULTS: We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well-studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium...
December 22, 2016: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28007029/arabidopsis-prc1-core-component-atring1-regulates-stem-cell-determining-carpel-development-mainly-through-repression-of-class-i-knox-genes
#14
Donghong Chen, Anne M Molitor, Lin Xu, Wen-Hui Shen
BACKGROUND: Polycomb repressive complex 2 (PRC2)-catalyzed H3K27me3 marks are tightly associated with the WUS-AG negative feedback loop to terminate floral stem cell fate to promote carpel development, but the roles of Polycomb repressive complex 1 (PRC1) in this event remain largely uncharacterized. RESULTS: Here we show conspicuous variability in the morphology and number of carpels among individual flowers in the absence of the PRC1 core components AtRING1a and AtRING1b, which contrasts with the wild-type floral meristem consumed by uniform carpel production in Arabidopsis thaliana...
December 22, 2016: BMC Biology
https://www.readbyqxmd.com/read/27998759/the-crispr-cas9-system-targeting-egfr-exon-17-abrogates-nf-%C3%AE%C2%BAb-activation-via-epigenetic-modulation-of-ubxn1-in-egfrwt-viii-glioma-cells
#15
Kai Huang, Chao Yang, Qi-Xue Wang, Yan-Sheng Li, Chuan Fang, Yan-Li Tan, Jian-Wei Wei, Yun-Fei Wang, Xin Li, Jun-Hu Zhou, Bing-Cong Zhou, Kai-Kai Yi, Kai-Liang Zhang, Jie Li, Chun-Sheng Kang
Worldwide, glioblastoma (GBM) is the most lethal and frequent intracranial tumor. Despite decades of study, the overall survival of GBM patients remains unchanged. epidermal growth factor receptor (EGFR) amplification and gene mutation are thought to be negatively correlated with prognosis. In this study, we used proteomics to determine that UBXN1 is a negative downstream regulator of the EGFR mutation vIII (EGFRvIII). Via bioinformatics analysis, we found that UBXN1 is a factor that can improve glioma patients' overall survival time...
December 18, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27993893/genome-wide-chip-seq-analysis-of-ezh2-mediated-h3k27me3-target-gene-profile-highlights-differences-between-low-and-high-grade-astrocytic-tumors
#16
Vikas Sharma, Prit Benny Malgulwar, Suvendu Purkait, Vikas Patil, Pankaj Pathak, Rahul Agarwal, Ritu Kulshreshtha, Supriya Mallick, Pramod Kumar Julka, Ashish Suri, Bhawani Shankar Sharma, Vaishali Suri, Mehar Chand Sharma, Chitra Sarkar
Enhancer of Zeste Homologue-2(EZH2) is a key epigenetic regulator that functions as oncogene and also known for inducing altered H3K27me3 mark in various tumors. However, H3K27me3 targets and their precise relationship with gene expression are largely unknown in astrocytic tumors. In this study, we checked EZH2 mRNA and protein expression in 90 astrocytic tumors of different grades using qPCR and IHC,respectively. Further, genome wide ChIP-seq analysis for H3K27me3 modification was also performed on 11 Glioblastomas(GBMs) and 2 Diffuse astrocytoma(DAs) samples...
December 17, 2016: Carcinogenesis
https://www.readbyqxmd.com/read/27992400/the-histone-demethylase-utx-regulates-the-lineage-specific-epigenetic-program-of-invariant-natural-killer-t-cells
#17
Semir Beyaz, Ji Hyung Kim, Luca Pinello, Michael E Xifaras, Yu Hu, Jialiang Huang, Marc A Kerenyi, Partha P Das, R Anthony Barnitz, Aurelie Herault, Rizkullah Dogum, W Nicholas Haining, Ömer H Yilmaz, Emmanuelle Passegue, Guo-Cheng Yuan, Stuart H Orkin, Florian Winau
Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of iNKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an iNKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX...
December 19, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27983539/lncrna-ancr-down-regulation-suppresses-invasion-and-migration-of-colorectal-cancer-cells-by-regulating-ezh2-expression
#18
Zhao-Yang Yang, Fang Yang, Ying-Li Zhang, Bao Liu, Meng Wang, Xuan Hong, Yan Yu, Yao-Hui Zhou, Hai Zeng
Our study aimed to explore the effects of long noncoding RNA (lncRNA)-ANCR on the invasion and migration of colorectal cancer (CRC) cells by regulating enhancer of zeste homolog 2 (EZH2) expression. CRC tissues and adjacent normal tissues were collected and CRC SW620 cells line and normal human intestinal epithelial cells (HIECs) were incubated. CRC SW620 cells line was transfected with ANCR-siRNA. The expressions of ANCR and EZH2 mRNA were measured by real-time quantitative polymerase chain reaction (RT-qPCR)...
December 9, 2016: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/27983522/different-expression-patterns-of-histone-h3k27-demethylases-in-renal-cell-carcinoma-and-bladder-cancer
#19
Zehui Hong, Hui Li, Lili Li, Weilong Wang, Ting Xu
OBJECTIVE: UTX and JMJD3 are recently identified histone H3 lysine 27 (H3K27) demethylases. Many studies have shown aberrant H3K27 trimethylation (H3K27me3) levels widely exist in multiple cancers, and that altered H3K27me3 levels are correlated with tumorigenesis and tumor progression. To investigate expression patterns of UTX and JMJD3 genes in renal cell carcinoma (RCC) and bladder cancer and the relationship between gene expression and tumor development. MATERIAL AND METHODS: Samples were collected from 35 patients with RCC and 21 patients with bladder cancer and qRT-PCR was performed...
December 9, 2016: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/27979710/hotair-facilitates-hepatic-stellate-cells-activation-and-fibrogenesis-in-the-liver
#20
Er-Bao Bian, Yuan-Yuan Wang, Yang Yang, Bao-Ming Wu, Tao Xu, Xiao-Ming Meng, Cheng Huang, Lei Zhang, Xiong-Wen Lv, Zhi-Gang Xiong, Jun Li
Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-β1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect...
December 13, 2016: Biochimica et Biophysica Acta
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