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https://www.readbyqxmd.com/read/29774579/integrative-epigenetic-analysis-reveals-therapeutic-targets-to-the-dna-methyltransferase-inhibitor-sgi-110-in-hepatocellular-carcinoma
#1
Minmin Liu, Lian Zhang, Hongtao Li, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony El-Khoueiry, John Daniels, Casey O'Connell, Tanya B Dorff, Qianjin Lu, Daniel J Weisenberger, Gangning Liang
There is an urgent need for developing more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2 and SNU475) were used to evaluate effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles and its clinical relevance by comparisons to TCGA HCC clinical data...
May 18, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29772549/long-non-coding-rna-and-polycomb-an-intricate-partnership-in-cancer-biology
#2
Cyrinne Achour, Francesca Aguilo
High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/29764982/superman-regulates-floral-whorl-boundaries-through-control-of-auxin-biosynthesis
#3
Yifeng Xu, Nathanaël Prunet, Eng-Seng Gan, Yanbin Wang, Darragh Stewart, Frank Wellmer, Jiangbo Huang, Nobutoshi Yamaguchi, Yoshitaka Tatsumi, Mikiko Kojima, Takatoshi Kiba, Hitoshi Sakakibara, Thomas P Jack, Elliot M Meyerowitz, Toshiro Ito
Proper floral patterning, including the number and position of floral organs in most plant species, is tightly controlled by the precise regulation of the persistence and size of floral meristems (FMs). In Arabidopsis , two known feedback pathways, one composed of WUSCHEL (WUS) and CLAVATA3 (CLV3) and the other composed of AGAMOUS (AG) and WUS, spatially and temporally control floral stem cells, respectively. However, mounting evidence suggests that other factors, including phytohormones, are also involved in floral meristem regulation...
May 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29759640/enhancer-of-zeste-homolog-2-ezh2-regulates-tumor-angiogenesis-and-predicts-recurrence-and-prognosis-of-intrahepatic-cholangiocarcinoma
#4
Shigeki Nakagawa, Hirohisa Okabe, Mayuko Ouchi, Ryuma Tokunaga, Naoki Umezaki, Takaaki Higashi, Takatoshi Kaida, Kota Arima, Yuki Kitano, Hideyuki Kuroki, Kosuke Mima, Hidetoshi Nitta, Katsunori Imai, Daisuke Hashimoto, Yo-Ichi Yamashita, Akira Chikamoto, Hideo Baba
BACKGROUND: Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). METHODS: The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays...
May 11, 2018: HPB: the Official Journal of the International Hepato Pancreato Biliary Association
https://www.readbyqxmd.com/read/29754954/the-polycomb-dependent-epigenome-controls-%C3%AE-cell-dysfunction-dedifferentiation-and-diabetes
#5
Tess Tsai-Hsiu Lu, Steffen Heyne, Erez Dror, Eduard Casas, Laura Leonhardt, Thorina Boenke, Chih-Hsiang Yang, Sagar, Laura Arrigoni, Kevin Dalgaard, Raffaele Teperino, Lennart Enders, Madhan Selvaraj, Marius Ruf, Sunil J Raja, Huafeng Xie, Ulrike Boenisch, Stuart H Orkin, Francis C Lynn, Brad G Hoffman, Dominic Grün, Tanya Vavouri, Adelheid M Lempradl, J Andrew Pospisilik
To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes...
May 4, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29741645/lsd1-coordinates-with-the-sin3a-hdac-complex-and-maintains-sensitivity-to-chemotherapy-in-breast-cancer
#6
Yang Yang, Wei Huang, Rongfang Qiu, Ruiqiong Liu, Yi Zeng, Jie Gao, Yu Zheng, Yongqiang Hou, Shuang Wang, Wenqian Yu, Shuai Leng, Dandan Feng, Yan Wang
Lysine-specific demethylase 1 (LSD1) was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcription regulation, recent studies indicate that LSD1 may coordinate with multiple epigenetic regulatory complexes including CoREST/HDAC complex, NuRD complex, SIRT1, and PRC2, implying complicated mechanistic actions of this seemingly simple enzyme. Here, we report that LSD1 is also an integral component of the SIN3A/HDAC complex...
May 7, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29736258/mtf2-prc2-control-of-canonical-wnt-signaling-is-required-for-definitive-erythropoiesis
#7
Janet L Manias Rothberg, Harinad B Maganti, Hani Jrade, Christopher J Porter, Gareth A Palidwor, Christopher Cafariello, Hannah L Battaion, Safwat T Khan, Theodore J Perkins, Robert F Paulson, Caryn Y Ito, William L Stanford
Polycomb repressive complex 2 (PRC2) accessory proteins play substoichiometric, tissue-specific roles to recruit PRC2 to specific genomic loci or increase enzymatic activity, while PRC2 core proteins are required for complex stability and global levels of trimethylation of histone 3 at lysine 27 (H3K27me3). Here, we demonstrate a role for the classical PRC2 accessory protein Mtf2/Pcl2 in the hematopoietic system that is more akin to that of a core PRC2 protein. Mtf2 -/- erythroid progenitors demonstrate markedly decreased core PRC2 protein levels and a global loss of H3K27me3 at promoter-proximal regions...
2018: Cell Discovery
https://www.readbyqxmd.com/read/29733847/structural-insight-into-the-role-of-val1-b3-domain-for-targeting-to-flc-locus-in-arabidopsis-thaliana
#8
Baixing Wu, Mengmeng Zhang, Shichen Su, Hehua Liu, Jianhua Gan, Jinbiao Ma
Vernalization is a pivotal stage for some plants involving many epigenetic changes during cold exposure. In Arabidopsis, an essential step in vernalization for further flowering is successful silence the potent floral repressor Flowering Locus C (FLC) by repressing histone mark. AtVal1 is a multi-function protein containing five domains that participate into many recognition processes and is validated to recruit the repress histone modifier PHD-PRC2 complex and interact with components of the ASAP complex target to the FLC nucleation region through recognizing a cis element known as CME (cold memory element) by its plant-specific B3 domain...
May 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29731341/architecture-of-prc2-holo-complexes
#9
Kendra R Vann, Tatiana G Kutateladze
Polycomb repressive complex 2 (PRC2) is a chief epigenetic regulator. In a new article, Chen et al. describe the crystal structure of the heterotetrameric PRC2 holo complex, which provides important mechanistic insights into the organization of its subunits and the association of PRC2 with chromatin.
May 3, 2018: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29727681/prc1-fine-tunes-gene-repression-and-activation-to-safeguard-skin-development-and-stem-cell-specification
#10
Idan Cohen, Dejian Zhao, Carmit Bar, Victor J Valdes, Katherine L Dauber-Decker, Minh Binh Nguyen, Manabu Nakayama, Michael Rendl, Wendy A Bickmore, Haruhiko Koseki, Deyou Zheng, Elena Ezhkova
Polycomb repressive complexes (PRCs) 1 and 2 are essential chromatin regulators of cell identity. PRC1, a dominant executer of Polycomb-mediated control, functions as multiple sub-complexes that possess catalytic-dependent H2AK119 mono-ubiquitination (H2AK119ub) and catalytic-independent activities. Here, we show that, despite its well-established repressor functions, PRC1 binds to both silent and active genes. Through in vivo loss-of-function studies, we show that global PRC1 function is essential for skin development and stem cell (SC) specification, whereas PRC1 catalytic activity is dispensable...
May 3, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29726819/histone-methyltransferase-ezh2-a-therapeutic-target-for-ovarian-cancer
#11
REVIEW
Bayley A Jones, Sooryanarayana Varambally, Rebecca C Arend
Ovarian cancer is the fifth leading cause of cancer-related deaths in females in the United States. There were an estimated 22,440 new cases and 14,080 deaths due to ovarian cancer in 2017. Most patients present with advanced-stage disease, revealing the urgent need for new therapeutic strategies targeting pathways of tumorigenesis and chemotherapy resistance. While multiple genomic changes contribute to the progression of this aggressive disease, it has become increasingly evident that epigenetic events play a pivotal role in ovarian cancer development...
March 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29707567/hotair-is-a-potential-novel-biomarker-in-patients-with-congenital-heart-diseases
#12
Yu Jiang, Hongdan Mo, Jing Luo, Suhong Zhao, Shuang Liang, Maomao Zhang, Jie Yuan
Objective: To investigate the expression of HOX transcript antisense RNA (HOTAIR) in cardiac tissues and plasma of patients with congenital heart diseases (CHDs). Methods: qRT-PCR was used to detect the expression of HOTAIR in right atrial appendage tissues of 16 patients with CHDs and 14 patients with rheumatic valvular heart diseases (RVHDs), as well as in plasma of 36 normal people and 90 patients with CHDs including 36 cases of ASD, 23 cases of VSD, and 31 cases of PDA...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29700471/telobox-motifs-recruit-clf-swn-prc2-for-h3k27me3-deposition-via-trb-factors-in-arabidopsis
#13
Yue Zhou, Yuejun Wang, Kristin Krause, Tingting Yang, Joram A Dongus, Yijing Zhang, Franziska Turck
Polycomb repressive complexes (PRCs) control organismic development in higher eukaryotes through epigenetic gene repression1-4 . PRC proteins do not contain DNA-binding domains, thus prompting questions regarding how PRCs find their target loci 5 . Here we present genome-wide evidence of PRC2 recruitment by telomere-repeat-binding factors (TRBs) through telobox-related motifs in Arabidopsis. A triple trb1-2, trb2-1, and trb3-2 (trb1/2/3) mutant with a developmental phenotype and a transcriptome strikingly similar to those of strong PRC2 mutants showed redistribution of trimethyl histone H3 Lys27 (H3K27me3) marks and lower H3K27me3 levels, which were correlated with derepression of TRB1-target genes...
April 26, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29695738/malat1-an-epigenetic-regulator-of-inflammation-in-diabetic-retinopathy
#14
Saumik Biswas, Anu Alice Thomas, Shali Chen, Erfan Aref-Eshghi, Biao Feng, John Gonder, Bekim Sadikovic, Subrata Chakrabarti
Despite possessing limited protein-coding potential, long non-coding RNAs (lncRNAs) have been implicated in a myriad of pathologic conditions. Most well documented in cancer, one prominent intergenic lncRNA known as MALAT1 is notorious for its role in impacting epigenetic mechanisms. In this study, we established a novel epigenetic paradigm for MALAT in diabetic retinopathy (DR) by employing siRNA-mediated MALAT1 knockdown in human retinal endothelial cells (HRECs), a Malat1 knockout animal model, vitreous humor from diabetic patients, pharmacological inhibitors for histone and DNA methylation, RNA immunoprecipitation, western blotting, and a unique DNA methylation array to determine glucose-related alterations in MALAT1...
April 25, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29685978/interplay-between-long-non-coding-rnas-and-epigenetic-machinery-emerging-targets-in-cancer
#15
REVIEW
David J Hanly, Manel Esteller, María Berdasco
Of the diverse array of putative molecular and biological functions assigned to long non-coding RNAs (lncRNAs), one attractive perspective in epigenetic research has been the hypothesis that lncRNAs directly interact with the proteins involved in the modulation of chromatin conformation. Indeed, epigenetic modifiers are among the most frequent protein partners of lncRNAs that have been identified to date, of which histone methyltransferases and protein members of the Polycomb Repressive Complex PRC2 have received considerable attention...
June 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29685965/pyrazole-based-inhibitors-of-enhancer-of-zeste-homologue-2-induce-apoptosis-and-autophagy-in-cancer-cells
#16
Paolo Mellini, Biagina Marrocco, Diana Borovika, Lucia Polletta, Ilaria Carnevale, Serena Saladini, Giulia Stazi, Clemens Zwergel, Peteris Trapencieris, Elisabetta Ferretti, Marco Tafani, Sergio Valente, Antonello Mai
Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o ( N -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1 H -pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy...
June 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29681499/allosteric-activation-dictates-prc2-activity-independent-of-its-recruitment-to-chromatin
#17
Chul-Hwan Lee, Jia-Ray Yu, Sunil Kumar, Ying Jin, Gary LeRoy, Natarajan Bhanu, Syuzo Kaneko, Benjamin A Garcia, Andrew D Hamilton, Danny Reinberg
PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome...
April 13, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29681498/distinct-stimulatory-mechanisms-regulate-the-catalytic-activity-of-polycomb-repressive-complex-2
#18
Chul-Hwan Lee, Marlene Holder, Daniel Grau, Ricardo Saldaña-Meyer, Jia-Ray Yu, Rais Ahmad Ganai, Jenny Zhang, Miao Wang, Gary LeRoy, Marc-Werner Dobenecker, Danny Reinberg, Karim-Jean Armache
The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs)...
April 13, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29670078/terra-recruitment-of-polycomb-to-telomeres-is-essential-for-histone-trymethylation-marks-at-telomeric-heterochromatin
#19
Juan J Montero, Isabel López-Silanes, Diego Megías, Mario F Fraga, Álvaro Castells-García, Maria A Blasco
TERRAs are long non-coding RNAs generated from the telomeres. Lack of TERRA knockout models has hampered understanding TERRAs' functions. We recently identified chromosome 20q as one of the main origins of human TERRAs, allowing us to generate the first 20q-TERRA knockout models and to demonstrate that TERRAs are essential for telomere length maintenance and protection. Here, we use ALT 20q-TERRA knockout cells to address a direct role of TERRAs in telomeric heterochromatin formation. We find that 20q-TERRAs are essential for the establishment of H3K9me3, H4K20me3, and H3K27me3 heterochromatin marks at telomeres...
April 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29667751/suz12-is-a-novel-putative-oncogene-promoting-tumorigenesis-in-head-and-neck-squamous-cell-carcinoma
#20
Yaping Wu, Huijun Hu, Wei Zhang, Zhongwu Li, Pengfei Diao, Dongmiao Wang, Wei Zhang, Yanling Wang, Jianrong Yang, Jie Cheng
The suppressor of zest 12 (SUZ12), one of the core polycomb repressive complex 2 (PRC2) components, has increasingly appreciated as a key mediator during human tumorigenesis. However, its expression pattern and oncogenic roles in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored yet. Here, we sought to determine its expression pattern, clinicopathological significance and biological roles in HNSCC. Through data mining and interrogation from multiple publicly available databases, our bioinformatics analyses revealed that SUZ12 mRNA was significantly overexpressed in multiple HNSCC patient cohorts...
April 18, 2018: Journal of Cellular and Molecular Medicine
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