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https://www.readbyqxmd.com/read/29764901/the-histone-demethylase-kdm5-is-essential-for-larval-growth-in-drosophila
#1
Coralie Drelon, Helen M Belalcazar, Julie Secombe
Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of transcriptional regulators are histone H3 lysine 4 demethylases that can function through both demethylase-dependent and independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells...
May 15, 2018: Genetics
https://www.readbyqxmd.com/read/29627262/structure-based-design-and-discovery-of-potent-and-selective-kdm5-inhibitors
#2
Zhe Nie, Lihong Shi, Chon Lai, Shawn M O'Connell, Jiangchun Xu, Ryan K Stansfield, David J Hosfield, James M Veal, Jeffrey A Stafford
Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1...
March 30, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29602065/targeting-histone-demethylases-kdm5a-and-kdm5b-in-aml-cancer-cells-a-comparative-view
#3
Gelareh Shokri, Shaghayegh Doudi, Mehrnoosh Fathi-Roudsari, Fatemeh Kouhkan, Mohammad-Hossein Sanati
Epigenetic modifications play an important role in initiation and progression of cancers including acute myeloid leukemia. Among different epigenetic modifiers, lysine specific demethylases have been noticed as potential therapeutic targets. KDM5 family of histone demethylases which removes methyl marks from lysine residues of H3, are frequently found in the promoter region of transcriptionally active genes resulting in repression of expression. Here we have compared the effects of KDM5A and KDM5B downregulation on HL-60 cell line behavior...
May 2018: Leukemia Research
https://www.readbyqxmd.com/read/29537847/insights-into-the-action-of-inhibitor-enantiomers-against-histone-lysine-demethylase-5a
#4
John R Horton, Xu Liu, Lizhen Wu, Kai Zhang, John Shanks, Xing Zhang, Ganesha Rai, Bryan T Mott, Daniel J Jansen, Stephen C Kales, Mark J Henderson, Katherine Pohida, Yuhong Fang, Xin Hu, Ajit Jadhav, David J Maloney, Matthew D Hall, Anton Simeonov, Haian Fu, Paula M Vertino, Qin Yan, Xiaodong Cheng
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, ( R)- and ( S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1 H-pyrrolo[3,2- b]pyridine-7-carboxylic acid (compounds N51 and N52) and ( R) - and ( S) -N-(1-(3-isopropyl-1 H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55)...
March 23, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29490272/a-drosophila-model-of-intellectual-disability-caused-by-mutations-in-the-histone-demethylase-kdm5
#5
Sumaira Zamurrad, Hayden A M Hatch, Coralie Drelon, Helen M Belalcazar, Julie Secombe
Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5A512P ). Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation...
February 27, 2018: Cell Reports
https://www.readbyqxmd.com/read/29372961/-coactivator-complexes-participate-in-different-stages-of-the-drosophila-melanogaster-hsp70-gene-transcription
#6
M Yu Mazina, P K Derevyanko, E V Kocheryzhkina, Yu V Nikolenko, A N Krasnov, N E Vorobyeva
The objective of this study was to identify transcriptional coactivators participating in transcription elongation of the hsp70 gene induced by heat shock. We found that all investigated coactivator complexes participate in transcription of this gene, as significant level of them were present at the gene promoter in its active state. For most of the coactivators (except for p300/CBP, Set2, and Mediator complex), we also observed a considerable increase of their binding level at the coding region of the gene after activation of its transcription by heat shock...
February 2017: Genetika
https://www.readbyqxmd.com/read/29282222/a-kdm5-inhibitor-increases-global-h3k4-trimethylation-occupancy-and-enhances-the-biological-efficacy-of-5-aza-2-deoxycytidine
#7
Benjamin R Leadem, Ioannis Kagiampakis, Catherine Wilson, Tommy K Cheung, David Arnott, Patrick Trojer, Marie Classon, Hariharan Easwaran, Stephen B Baylin
The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes...
December 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29233856/structure-of-the-arabidopsis-jmj14-h3k4me3-complex-provides-insight-into-the-substrate-specificity-of-kdm5-subfamily-histone-demethylases
#8
Zhenlin Yang, Qi Qiu, Wei Chen, Bei Jia, Xiaomei Chen, Hongmiao Hu, Kaixuan He, Xian Deng, Sisi Li, W Andy Tao, Xiaofeng Cao, Jiamu Du
In chromatin, histone methylation affects the epigenetic regulation of multiple processes in animals and plants and is modulated by the activities of histone methyltransferases and histone demethylases. The jumonji domain-containing histone demethylases have diverse functions and can be classified into several subfamilies. In humans, the jumonji domain-containing Lysine (K)-Specific Demethylase 5/Jumonji and ARID Domain Protein (KDM5/JARID) subfamily demethylases are specific for histone 3 lysine 4 trimethylation (H3K4me3) and are important drug targets for cancer treatment...
January 2018: Plant Cell
https://www.readbyqxmd.com/read/28827290/kinetochore-components-required-for-centromeric-chromatin-assembly-are-impacted-by-msc1-in-schizosaccharomyces-pombe
#9
Chenchao Gao, Lauren Langbein, Fariha Kamal, Anuja A George, Nancy C Walworth
Eukaryotic chromosome segregation requires a protein complex known as the kinetochore that mediates attachment between mitotic spindle microtubules and centromere-specific nucleosomes composed of the widely conserved histone variant CENP-A. Mutations in kinetochore proteins of the fission yeast Schizosaccharomyces pombe lead to chromosome missegregation such that daughter cells emerge from mitosis with unequal DNA content. We find that multiple copies of Msc1-a fission yeast homolog of the KDM5 family of proteins-suppresses the temperature-sensitive growth defect of several kinetochore mutants, including mis16 and mis18 , as well as mis6 , mis15 , and mis17 , components of the Constitutive Centromere Associated Network (CCAN)...
October 2017: Genetics
https://www.readbyqxmd.com/read/28827149/studies-on-the-interaction-of-the-histone-demethylase-kdm5b-with-tricarboxylic-acid-cycle-intermediates
#10
Hanna Tarhonskaya, Radosław P Nowak, Catrine Johansson, Aleksandra Szykowska, Anthony Tumber, Rebecca L Hancock, Pauline Lang, Emily Flashman, Udo Oppermann, Christopher J Schofield, Akane Kawamura
Methylation of lysine-4 of histone H3 (H3K4men ) is an important regulatory factor in eukaryotic transcription. Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. Altered levels of tricarboxylic acid (TCA) cycle intermediates and the associated metabolites D- and L-2-hydroxyglutarate (2HG) can cause changes in chromatin methylation status...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28587163/a-tox21-approach-to-altered-epigenetic-landscapes-assessing-epigenetic-toxicity-pathways-leading-to-altered-gene-expression-and-oncogenic-transformation-in-vitro
#11
REVIEW
Craig L Parfett, Daniel Desaulniers
An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs...
June 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28512031/from-a-novel-hts-hit-to-potent-selective-and-orally-bioavailable-kdm5-inhibitors
#12
Jun Liang, Sharada Labadie, Birong Zhang, Daniel F Ortwine, Snahel Patel, Maia Vinogradova, James R Kiefer, Till Mauer, Victor S Gehling, Jean-Christophe Harmange, Richard Cummings, Tommy Lai, Jiangpeng Liao, Xiaoping Zheng, Yichin Liu, Amy Gustafson, Erica Van der Porten, Weifeng Mao, Bianca M Liederer, Gauri Deshmukh, Le An, Yingqing Ran, Marie Classon, Patrick Trojer, Peter S Dragovich, Lesley Murray
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit...
July 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#13
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
July 18, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28262558/potent-and-selective-kdm5-inhibitor-stops-cellular-demethylation-of-h3k4me3-at-transcription-start-sites-and-proliferation-of-mm1s-myeloma-cells
#14
Anthony Tumber, Andrea Nuzzi, Edward S Hookway, Stephanie B Hatch, Srikannathasan Velupillai, Catrine Johansson, Akane Kawamura, Pavel Savitsky, Clarence Yapp, Aleksandra Szykowska, Na Wu, Chas Bountra, Claire Strain-Damerell, Nicola A Burgess-Brown, Gian Filippo Ruda, Oleg Fedorov, Shonagh Munro, Katherine S England, Radoslaw P Nowak, Christopher J Schofield, Nicholas B La Thangue, Charlotte Pawlyn, Faith Davies, Gareth Morgan, Nick Athanasou, Susanne Müller, Udo Oppermann, Paul E Brennan
Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+ -dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28138513/kdm5-lysine-demethylases-are-involved-in-maintenance-of-3-utr-length
#15
Lauren P Blair, Zongzhi Liu, Ramon Lorenzo D Labitigan, Lizhen Wu, Dinghai Zheng, Zheng Xia, Erica L Pearson, Fathima I Nazeer, Jian Cao, Sabine M Lang, Rachel J Rines, Samuel G Mackintosh, Claire L Moore, Wei Li, Bin Tian, Alan J Tackett, Qin Yan
The complexity by which cells regulate gene and protein expression is multifaceted and intricate. Regulation of 3' untranslated region (UTR) processing of mRNA has been shown to play a critical role in development and disease. However, the process by which cells select alternative mRNA forms is not well understood. We discovered that the Saccharomyces cerevisiae lysine demethylase, Jhd2 (also known as KDM5), recruits 3'UTR processing machinery and promotes alteration of 3'UTR length for some genes in a demethylase-dependent manner...
November 2016: Science Advances
https://www.readbyqxmd.com/read/27899593/the-kdm5-family-is-required-for-activation-of-pro-proliferative-cell-cycle-genes-during-adipocyte-differentiation
#16
Ann-Sofie B Brier, Anne Loft, Jesper G S Madsen, Thomas Rosengren, Ronni Nielsen, Søren F Schmidt, Zongzhi Liu, Qin Yan, Hinrich Gronemeyer, Susanne Mandrup
The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se...
February 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27882807/jarid1-kdm5-demethylases-as-cancer-targets
#17
Joyce Taylor-Papadimitriou, Joy Burchell
No abstract text is available yet for this article.
January 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/27866838/glutaminolysis-and-fumarate-accumulation-integrate-immunometabolic-and-epigenetic-programs-in-trained-immunity
#18
Rob J W Arts, Boris Novakovic, Rob Ter Horst, Agostinho Carvalho, Siroon Bekkering, Ekta Lachmandas, Fernando Rodrigues, Ricardo Silvestre, Shih-Chin Cheng, Shuang-Yin Wang, Ehsan Habibi, Luís G Gonçalves, Inês Mesquita, Cristina Cunha, Arjan van Laarhoven, Frank L van de Veerdonk, David L Williams, Jos W M van der Meer, Colin Logie, Luke A O'Neill, Charles A Dinarello, Niels P Riksen, Reinout van Crevel, Clary Clish, Richard A Notebaart, Leo A B Joosten, Hendrik G Stunnenberg, Ramnik J Xavier, Mihai G Netea
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases...
December 13, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27618572/pyrido-3-4-d-pyrimidin-4-3h-one-metabolism-mediated-by-aldehyde-oxidase-is-blocked-by-c2-substitution
#19
Angela Hayes, N Yi Mok, Manjuan Liu, Ching Thai, Alan T Henley, Butrus Atrash, Rachel M Lanigan, Jemmy Sejberg, Yann-Vaï Le Bihan, Vassilios Bavetsias, Julian Blagg, Florence I Raynaud
1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and (1)H-NMR and showed that C2-substituted derivatives are no longer AO substrates...
September 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27578789/impaired-removal-of-h3k4-methylation-affects-cell-fate-determination-and-gene-transcription
#20
Yvonne C Lussi, Luca Mariani, Carsten Friis, Juhani Peltonen, Toshia R Myers, Claudia Krag, Garry Wong, Anna Elisabetta Salcini
Methylation of histone 3 lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway...
October 15, 2016: Development
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