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Histone demethylases

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https://www.readbyqxmd.com/read/28228757/regulation-of-epigenetic-modifiers-including-kdm6b-by-interferon-%C3%AE-and-interleukin-4-in-human-macrophages
#1
Gökçe Yıldırım-Buharalıoğlu, Mark Bond, Graciela B Sala-Newby, Charles C T Hindmarch, Andrew C Newby
BACKGROUND: Interferon-γ (IFN-γ) or interleukin-4 (IL-4) drives widely different transcriptional programs in macrophages. However, how IFN-γ and IL-4 alter expression of histone-modifying enzymes involved in epigenetic regulation and how this affects the resulting phenotypic polarization is incompletely understood. METHODS AND RESULTS: We investigated steady-state messenger RNA levels of 84 histone-modifying enzymes and related regulators in colony-stimulating factor-1 differentiated primary human macrophages using quantitative polymerase chain reaction...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28228264/lsd1-controls-timely-myod-expression-via-myod-core-enhancer-transcription
#2
Isabella Scionti, Shinichiro Hayashi, Sandrine Mouradian, Emmanuelle Girard, Joana Esteves de Lima, Véronique Morel, Thomas Simonet, Maud Wurmser, Pascal Maire, Katia Ancelin, Eric Metzger, Roland Schüle, Evelyne Goillot, Frederic Relaix, Laurent Schaeffer
MyoD is a master regulator of myogenesis. Chromatin modifications required to trigger MyoD expression are still poorly described. Here, we demonstrate that the histone demethylase LSD1/KDM1a is recruited on the MyoD core enhancer upon muscle differentiation. Depletion of Lsd1 in myoblasts precludes the removal of H3K9 methylation and the recruitment of RNA polymerase II on the core enhancer, thereby preventing transcription of the non-coding enhancer RNA required for MyoD expression (CEeRNA). Consistently, Lsd1 conditional inactivation in muscle progenitor cells during embryogenesis prevented transcription of the CEeRNA and delayed MyoD expression...
February 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28223039/oncogene-lsd1-is-epigenetically-suppressed-by-mir-137-overexpression-in-human-non-small-cell-lung-cancer
#3
Xin Zhang, Xiujuan Zhang, Bo Yu, Rongpeng Hu, Lanxiang Hao
PURPOSE: We examined the epigenetic regulation of microRNA-137 (miR-137) on lysine-specific demethylase 1 (KDM1A, or LSD1) induced oncogenic effects in NSCLC. METHODS: NSCLC cell lines, A549 and H460 cells were transfected with a mammalian LSD1 overexpression plasmid. It's effects on endogenous KDM1A gene and LSD1 protein expressions were examined by qRT-PCR and western blot assays. NSCLC proliferation and migration were also examined by MTT proliferation and wound-scratch assays, respectively...
February 18, 2017: Biochimie
https://www.readbyqxmd.com/read/28219005/a-rhodium-iii-based-inhibitor-of-lysine-specific-histone-demethylase-1-as-an-epigenetic-modulator-in-prostate-cancer-cells
#4
Chao Yang, Wanhe Wang, Jiaxin Liang, Guodong Li, Kasipandi Vellaisamy, Chun-Yuen Wong, Dik-Lung Ma, Chung-Hang Leung
We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells, and enhanced the amplification of p21, FOXA2 and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7 and MAO activities, and also showed anti-proliferative activity towards human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28218462/tungsten-exposure-causes-a-selective-loss-of-histone-demethylase-protein
#5
Freda Laulicht Glick, Feng Wu, Xiaoru Zhang, Ashley Jordan, Jason Brocato, Thomas Kluz, Hong Sun, Max Costa
In the course of our investigations into the toxicity of tungstate, we discovered that cellular exposure resulted in the loss of the histone demethylase protein. We specifically investigated the loss of two histone demethylase dioxygenases, JARID1A and JMJD1A. Both of these proteins were degraded in the presence of tungstate and this resulted in increased global levels of H3K4me3 and H3K9me2, the substrates of JARID1A and JMJD1A respectively. Treatment with MG132 completely inhibited the loss of the demethylase proteins induced by tungstate treatment, suggesting that tungstate activated the proteasomal degradation of these proteins...
February 20, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28212444/sumo-modification-of-a-heterochromatin-histone-demethylase-jmjd2a-enables-viral-gene-transactivation-and-viral-replication
#6
Wan-Shan Yang, Mel Campbell, Pei-Ching Chang
Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi's sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation...
February 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28210006/a-novel-lsd1-inhibitor-ncd38-ameliorates-mds-related-leukemia-with-complex-karyotype-by-attenuating-leukemia-programs-via-activating-super-enhancers
#7
N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDS) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28209718/demethylation-of-h3k27-is-essential-for-the-induction-of-direct-cardiac-reprogramming-by-mir-combo
#8
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/28205605/the-role-of-the-rna-demethylase-fto-fat-mass-and-obesity-associated-and-mrna-methylation-in-hippocampal-memory-formation
#9
Brandon J Walters, Valentina Mercaldo, Colleen J Gillon, Matthew Yip, Rachael L Neve, Frederick M Boyce, Paul W Frankland, Sheena A Josselyn
The formation of long-lasting memories requires coordinated changes in gene expression and protein synthesis (Davis and Squire, 1984; Duvarci et al, 2008; Hernandez and Abel, 2008). Although many studies implicate DNA modifications (DNA methylation, histone modifications) in memory formation, the contributions of RNA modifications remain largely unexplored. Here, we investigated the role of mRNA methylation in hippocampal-dependent memory formation in mice. RNA modifications are highly dynamic and readily reversible (Jia et al, 2013)...
February 16, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28193778/ag-221-a-first-in-class-therapy-targeting-acute-myeloid-leukemia-harboring-oncogenic-idh2-mutations
#10
Katharine Yen, Jeremy Travins, Fang Wang, Muriel D David, Erin Artin, Kim Straley, Anil Padyana, Stefan Gross, Byron DeLaBarre, Erica Tobin, Yue Chen, Raj Nagaraja, Sung Choe, Lei Jin, Zenon Konteatis, Giovanni Cianchetta, Jeffrey O Saunders, Francesco G Salituro, Cyril Quivoron, Paule Opolon, Olivia Bawa, Véronique Saada, Angelo Paci, Sophie Broutin, Olivier A Bernard, Stéphane de Botton, Benoît S Marteyn, Monika Pilichowska, YingXia Xu, Cheng Fang, Fan Jiang, Wentao Wei, Shengfang Jin, Lee Silverman, Wei Liu, Hua Yang, Lenny Dang, Marion Dorsch, Virginie Penard-Lacronique, Scott A Biller, Shin-San Michael Su
Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite, (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the Tet family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28188179/new-insights-into-the-role-of-jmjd3-and-utx-in-axial-skeletal-formation-in-mice
#11
Chie Naruse, Shinwa Shibata, Masaru Tamura, Takayuki Kawaguchi, Kanae Abe, Kazushi Sugihara, Tomoaki Kato, Takumi Nishiuchi, Shigeharu Wakana, Masahito Ikawa, Masahide Asano
Jmjd3 and Utx are demethylases specific for lysine 27 of histone H3. Previous reports indicate that Jmjd3 is essential for differentiation of various cell types, such as macrophages and epidermal cells in mice, whereas Utx is involved in cancer and developmental diseases in humans and mice as well as Hox regulation in zebrafish and nematodes. Here, we report that Jmjd3, but not Utx, is involved in axial skeletal formation in mice. A Jmjd3 mutant embryo (Jmjd3(Δ18/Δ18)), but not a catalytically inactive Utx truncation mutant (Utx(-/y)), showed anterior homeotic transformation...
February 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28186757/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-2-structure-based-drug-design-and-structure-activity-relationship
#12
Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Oronza A Botrugno, Manuela Villa, Paola Dessanti, Saverio Minucci, Stefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1) the identification of thieno[3,2-b]pyrrole-5-carboxamides, as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series, based on multiple ligand/KDM1A-CoRest co-crystal structures, which led to several extremely potent inhibitors...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28186755/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-1-high-throughput-screening-and-preliminary-exploration
#13
Luca Sartori, Ciro Mercurio, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Stefania Vultaggio, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Elisa Zagarrí, Daniele Carettoni, Lucia Iuzzolino, Mario Varasi, Paola Vianello
Lysine specific demethylase 1 KDM1A (LSD1) is one regulator of histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying 4 chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28181538/epigenetic-editing-of-ascl1-gene-in-neural-stem-cells-by-optogenetics
#14
Chiao-Ling Lo, Samrat Roy Choudhury, Joseph Irudayaraj, Feng C Zhou
Enzymes involved in epigenetic processes such as methyltransferases or demethylases are becoming highly utilized for their persistent DNA or histone modifying efficacy. Herein, we have developed an optogenetic toolbox fused to the catalytic domain (CD) of DNA-methyltransferase3A (DNMT3A-CD) or Ten-Eleven Dioxygenase-1 (TET1-CD) for loci-specific alteration of the methylation state at the promoter of Ascl1 (Mash1), a candidate proneuron gene. Optogenetical protein pairs, CRY2 linked to DNMT3A-CD or TET1-CD and CIB1 fused to a Transcription Activator-Like Element (TALE) locating an Ascl1 promoter region, were designed for site specific epigenetic editing...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28177890/long-noncoding-rna-hotair-promotes-metastasis-of-renal-cell-carcinoma-by-up-regulating-histone-h3k27-demethylase-jmjd3
#15
Ming Xia, Lv Yao, Qiaoxia Zhang, Feng Wang, Hongbin Mei, Xiaoqiang Guo, Weiren Huang
Long Noncoding RNAs (lncRNAs) are a kind of non-protein coding transcripts longer than 200 nucleotides, and play important roles in diverse biological processes, such as embryonic development and apoptosis. Homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) is a negative prognostic factor in a variety of human cancers, such as breast, liver and lung cancers. HOTAIR can promote cancer cell metastasis by reprogramming chromatin organization. In the present study, HOTAIR expression was elevated in tissues of renal cell carcinoma compared to adjacent normal tissues, and positively correlated with metastasis (P<0...
February 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28158205/structure-activity-relationship-and-modeling-studies-of-inhibitors-of-lysine-specific-demethylase-1
#16
Chao Zhou, Fangrui Wu, Lianghao Lu, Liping Wei, Eric Pai, Yuan Yao, Yongcheng Song
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B...
2017: PloS One
https://www.readbyqxmd.com/read/28152483/lsd1-collaborates-with-ezh2-to-regulate-expression-of-interferon-stimulated-genes
#17
Yue Jin, Bo Huo, Xueqi Fu, Tian Hao, Yu Zhang, Yidi Guo, Xin Hu
Histone methylation is a complicate and dynamic epigenetic modification that regulates gene transcription, chromosomal structure and cell differentiation. Here, we discovered the interaction between the H3K4 demethylase, lysine specific demethylase 1 (LSD1, an important component of CoREST repressor complex) and the H3K27 methyltransferase, enhancer of zeste homolog 2 (EZH2, an essential component of PRC2). Immuno-precipitation and GST-pull down assay were performed to observe the interaction between the proteins...
January 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28150810/differential-lactate-and-cholesterol-synthetic-activities-in-xy-and-xx-sertoli-cells
#18
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/28148649/c3g-shows-regulated-nucleo-cytoplasmic-exchange-and-represses-histone-modifications-associated-with-euchromatin
#19
Dhruv Kumar Shakyawar, Kunal Dayma, Anesh Ramadhas, Chavvakula Varalakshmi, Vegesna Radha
C3G (RapGEF1) is a ubiquitously expressed guanine nucleotide exchange factor that functions in signaling pathways regulating cell proliferation, apoptosis, and actin reorganization. It is essential for differentiation, and early embryonic development in mice. Over-expressed C3G shows predominant cytoplasmic localization, but endogenous C3G is a component of nuclear fractions in a variety of cell types. Co-expression of Importin-α and inhibition of nuclear export by Leptomycin B resulted in predominant nuclear localization of C3G...
February 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28144654/the-small-molecule-jib-04-disrupts-o2-binding-in-the-fe-dependent-histone-demethylase-kdm4a-jmjd2a
#20
Barbara Cascella, Soon Goo Lee, Sukrit Singh, Joseph M Jez, Liviu M Mirica
JIB-04, a specific inhibitor of the O2-activating, Fe-dependent histone lysine demethylases, is revealed to disrupt the binding of O2 in KDM4A/JMJD2A through a continuous O2-consumption assay, X-ray crystal structure data, and molecular docking.
February 9, 2017: Chemical Communications: Chem Comm
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