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https://www.readbyqxmd.com/read/28230279/folate-protects-hepatocytes-of-hyperhomocysteinemia-mice-from-apoptosis-via-cystic-fibrosis-transmembrane-conductance-regulator-cftr-activated-endoplasmic-reticulum-stress
#1
Anning Yang, Yue Sun, Caiyan Mao, Songhao Yang, Min Huang, Mei Deng, Ning Ding, Xiaoling Yang, Minghao Zhang, Shaoju Jin, Yideng Jiang, Ying Huang
Folate deficiency is a known risk factor for liver injury; however, the underlying mechanism remains unclear. In this study, we employed a high homocysteine-induced liver injury model of Apolipoprotein E-deficient (ApoE(-/-) ) mice fed high-methionine diet and found that high homocysteine induced endoplasmic reticulum (ER) stress and liver cell apoptosis by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression; observations that were attenuated with supplementation of dietary folate...
February 23, 2017: Journal of Cellular Biochemistry
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
#2
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/28223506/intragenic-cpg-islands-play-important-roles-in-bivalent-chromatin-assembly-of-developmental-genes
#3
Sun-Min Lee, Jungwoo Lee, Kyung-Min Noh, Won-Young Choi, Sejin Jeon, Goo Taeg Oh, Jeongsil Kim-Ha, Yoonhee Jin, Seung-Woo Cho, Young-Joon Kim
CpG, 5'-C-phosphate-G-3', islands (CGIs) have long been known for their association with enhancers, silencers, and promoters, and for their epigenetic signatures. They are maintained in embryonic stem cells (ESCs) in a poised but inactive state via the formation of bivalent chromatin containing both active and repressive marks. CGIs also occur within coding sequences, where their functional role has remained obscure. Intragenic CGIs (iCGIs) are largely absent from housekeeping genes, but they are found in all genes associated with organ development and cell lineage control...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28223321/a-non-canonical-function-of-ezh2-preserves-immune-homeostasis
#4
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
#5
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
#6
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
#7
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/28209164/rnf40-regulates-gene-expression-in-an-epigenetic-context-dependent-manner
#8
Wanhua Xie, Sankari Nagarajan, Simon J Baumgart, Robyn Laura Kosinsky, Zeynab Najafova, Vijayalakshmi Kari, Magali Hennion, Daniela Indenbirken, Stefan Bonn, Adam Grundhoff, Florian Wegwitz, Ahmed Mansouri, Steven A Johnsen
BACKGROUND: Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. RESULTS: Using conditional Rnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss...
February 16, 2017: Genome Biology
https://www.readbyqxmd.com/read/28196596/chemosensitive-relapse-in-small-cell-lung-cancer-proceeds-through-an-ezh2-slfn11-axis
#9
Eric E Gardner, Benjamin H Lok, Valentina E Schneeberger, Patrice Desmeules, Linde A Miles, Paige K Arnold, Andy Ni, Inna Khodos, Elisa de Stanchina, Thuyen Nguyen, Julien Sage, John E Campbell, Scott Ribich, Natasha Rekhtman, Afshin Dowlati, Pierre P Massion, Charles M Rudin, John T Poirier
Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28195122/integrated-genomic-analyses-of-de-novo-pathways-underlying-atypical-meningiomas
#10
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
#11
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/28193775/targeting-the-eed-h3k27me3-interaction-allosterically-inhibits-prc2
#12
(no author information available yet)
EED226 and A-395 bind to the H3K27me3 binding pocket of EED to allosterically inhibit PRC2.
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28167662/impaired-ire1-expression-and-xbp1-activation-is-a-hallmark-of-gcb-dlbcl-and-contributes-to-tumor-growth
#13
Bojan Bujisic, Aude De Gassart, Rémy Tallant, Olivier Demaria, Léa Zaffalon, Sonia Chelbi, Michel Gilliet, Francesco Bertoni, Fabio Martinon
The endoplasmic reticulum kinase IRE1 and its downstream target XBP1 drive B cell differentiation towards plasma cells and have been shown to contribute to multiple myeloma development; yet little is known on the role of this pathway in Diffuse Large B cell Lymphoma (DLBCL). Here we show that in Germinal Center B cell-like (GCB) DLBCL subtype, IRE1 expression is reduced to a level that prevents XBP1 activation. Gene expression profiles indicated that, in GCB DLBCL cancer samples, expression of IRE1 mRNA was inversely correlated with the levels and activity of the epigenetic repressor, histone methyltransferase EZH2...
February 6, 2017: Blood
https://www.readbyqxmd.com/read/28165227/discovery-of-peptidomimetic-ligands-of-eed-as-allosteric-inhibitors-of-prc2
#14
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/28155862/synergetic-effects-of-dna-methylation-and-histone-modification-during-mouse-induced-pluripotent-stem-cell-generation
#15
Guiying Wang, Rong Weng, Yuanyuan Lan, Xudong Guo, Qidong Liu, Xiaoqin Liu, Chenqi Lu, Jiuhong Kang
DNA methylation and histone methylation (H3K27me3) have been reported as major barriers to induced pluripotent stem cell (iPSC) generation using four core transcription factors (Oct4, Sox2, Klf4, and c-Myc, termed OSKM). Here, to illustrate the possibility of deriving iPSCs via demethylation, as well as the exact effects of DNA methylation and histone modification on gene expression regulation, we performed RNA sequencing to characterize the transcriptomes of ES cells and iPSCs derived by demethylation with miR-29b or shDnmt3a, and carried out integrated analyses...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28155248/mutants-in-the-imprinted-pickle-related-2-gene-suppress-seed-abortion-of-fertilization-independent-seed-class-mutants-and-paternal-excess-interploidy-crosses-in-arabidopsis
#16
Fang Huang, Qian-Hao Zhu, Anyu Zhu, Xiaoba Wu, Liqiong Xie, Xianjun Wu, Chris Helliwell, Abed Chaudhury, E Jean Finnegan, Ming Luo
Endosperm cellularization is essential for embryo development and viable seed formation. Loss of function of the FERTILIZATION INDEPENDENT SEED (FIS) class Polycomb genes, which mediate histone H3 lysine27 trimethylation (H3K27me3), as well as imbalanced contributions of parental genomes interrupt this process. What causes the failure of cellularization is poorly understood. In this study, we identified PICKLE RELATED 2 (PKR2), mutations which suppress seed abortion in fis1/mea by restoring endosperm cellularization...
February 3, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28150810/differential-lactate-and-cholesterol-synthetic-activities-in-xy-and-xx-sertoli-cells
#17
Yurina Shishido, Takashi Baba, Tetsuya Sato, Yuichi Shima, Kanako Miyabayashi, Miki Inoue, Haruhiko Akiyama, Hiroshi Kimura, Yoshiakira Kanai, Yasuhiro Ishihara, Shogo Haraguchi, Akira Miyazaki, Damjana Rozman, Takeshi Yamazaki, Man-Ho Choi, Yasuyuki Ohkawa, Mikita Suyama, Ken-Ichirou Morohashi
SRY, a sex-determining gene, induces testis development in chromosomally female (XX) individuals. However, mouse XX Sertoli cells carrying Sry (XX/Sry Sertoli cells) are incapable of fully supporting germ cell development, even when the karyotype of the germ cells is XY. While it has therefore been assumed that XX/Sry Sertoli cells are not functionally equivalent to XY Sertoli cells, it has remained unclear which specific functions are affected. To elucidate the functional difference, we compared the gene expression of XY and XX/Sry Sertoli cells...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28148216/histone-h3-lysine-27-trimethylation-leads-to-loss-of-mesendodermal-competence-during-gastrulation-in-zebrafish-ectodermal-cells
#18
Taishi Shiomi, Akihiko Muto, Shunya Hozumi, Hiroshi Kimura, Yutaka Kikuchi
Previous studies in Xenopus have shown that forced expression of Nodal signaling can change ectodermal cells to a mesodermal fate by the early gastrula stage, suggesting mesodermal competence in early ectoderm cells. This mesodermal competence in ectodermal cells has been shown to be regulated at the level of nucleocytoplasmic localization of Smad2 in Xenopus. However, the regulation of mesodermal competence through epigenetic mechanisms has not been fully elucidated. Here, we used a constitutively active form of zebrafish Smad2 (Smad2ca) to overcome the inhibition of Nodal signaling via the nuclear exclusion of Smad2...
February 2017: Zoological Science
https://www.readbyqxmd.com/read/28135237/the-eed-protein-protein-interaction-inhibitor-a-395-inactivates-the-prc2-complex
#19
Yupeng He, Sujatha Selvaraju, Michael L Curtin, Clarissa G Jakob, Haizhong Zhu, Kenneth M Comess, Bailin Shaw, Juliana The, Evelyne Lima-Fernandes, Magdalena M Szewczyk, Dong Cheng, Kelly L Klinge, Huan-Qiu Li, Marina Pliushchev, Mikkel A Algire, David Maag, Jun Guo, Justin Dietrich, Sanjay C Panchal, Andrew M Petros, Ramzi F Sweis, Maricel Torrent, Lance J Bigelow, Guillermo Senisterra, Fengling Li, Steven Kennedy, Qin Wu, Donald J Osterling, David J Lindley, Wenqing Gao, Scott Galasinski, Dalia Barsyte-Lovejoy, Masoud Vedadi, Fritz G Buchanan, Cheryl H Arrowsmith, Gary G Chiang, Chaohong Sun, William N Pappano
Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2...
January 30, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28135235/an-allosteric-prc2-inhibitor-targeting-the-h3k27me3-binding-pocket-of-eed
#20
Wei Qi, Kehao Zhao, Justin Gu, Ying Huang, Youzhen Wang, Hailong Zhang, Man Zhang, Jeff Zhang, Zhengtian Yu, Ling Li, Lin Teng, Shannon Chuai, Chao Zhang, Mengxi Zhao, HoMan Chan, Zijun Chen, Douglas Fang, Qi Fei, Leying Feng, Lijian Feng, Yuan Gao, Hui Ge, Xinjian Ge, Guobin Li, Andreas Lingel, Ying Lin, Yueqin Liu, Fangjun Luo, Minlong Shi, Long Wang, Zhaofu Wang, Yanyan Yu, Jue Zeng, Chenhui Zeng, Lijun Zhang, Qiong Zhang, Shaolian Zhou, Counde Oyang, Peter Atadja, En Li
Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED...
January 30, 2017: Nature Chemical Biology
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