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Histone demethylation

Rohit Mathur, Lalit Sehgal, Ondrej Havranek, Stefan Köhrer, Tamer Khashab, Neeraj Jain, Jan A Burger, Sattva S Neelapu, R Eric Davis, Felipe Samaniego
Histone methylation and demethylation regulates B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting curative rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in-vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the DLBCL germinal center B-cell subtype, and higher KDM6B levels are associated with worse survival in DLBCL patients treated with R-CHOP...
October 14, 2016: Haematologica
Xin Li, Yun Liu, Tal Salz, Kasper D Hansen, Andrew P Feinberg
DNA methylation at the 5-postion of cytosine (5mC) is an epigenetic modification that regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family oxidizes 5mC to 5-hydroxymethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer...
October 13, 2016: Genome Research
Nathalie Dehne, Bernhard Brüne
Hypoxia, by activating transcription factors induces transcription of some genes but it also reduces mRNA synthesis by mechanisms that are poorly defined. Activation of human macrophages with interleukin (IL)-4 showed that up-regulation of some IL-4 target genes was reduced when macrophages were incubated at 1% oxygen. Hypoxia impaired induction of chemokine (C-C motif) ligand 18 (CCL18), although IL-4-induced DNA binding of the transcription factor STAT6 remained intact. In contrast, induction of serine peptidase inhibitor, Kunitz type (SPINT)2, another IL-4/STAT6 target gene, was not affected by hypoxia...
October 11, 2016: Biochimica et Biophysica Acta
Nicolás Herranz, Natàlia Dave, Alba Millanes-Romero, Laura Pascual, Lluis Morey, Víctor M Díaz, Víctor Lórenz-Fonfría, Ricardo Gutierrez-Gallego, Celia Jerónimo, Ane Iturbide, Luciano Di Croce, Antonio García de Herreros, Sandra Peiró
Methylation of histone H3 lysine 4 is linked to active transcription and can be removed by LSD1 or the JmjC domain-containing proteins by amino-oxidation or hydroxylation, respectively. Here we describe that its deamination can be catalyzed by lysyl oxidase-like 2 protein (LOXL2), presenting an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, by regulating H3K4me3 deamination, LOXL2 activity is linked with the transcriptional control of the CDH1 gene...
October 13, 2016: FEBS Journal
Jianing Zhong, Xianfeng Li, Wanshi Cai, Yan Wang, Shanshan Dong, Jie Yang, Jian'an Zhang, Nana Wu, Yuanyuan Li, Fengbiao Mao, Cheng Zeng, Jinyu Wu, Xingzhi Xu, Zhong Sheng Sun
The Ten Eleven Translocation 1 (TET1) protein is a DNA demethylase that regulates gene expression through altering statue of DNA methylation. However, recent studies have demonstrated that TET1 could modulate transcriptional expression independent of its DNA demethylation activity; yet, the detailed mechanisms underlying TET1's role in such transcriptional regulation remain not well understood. Here, we uncovered that Tet1 formed a chromatin complex with histone acetyltransferase Mof and scaffold protein Sin3a in mouse embryonic stem cells by integrative genomic analysis using publicly available ChIP-seq data sets and a series of in vitro biochemical studies in human cell lines...
October 12, 2016: Nucleic Acids Research
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics plays a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic and functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here, we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 11, 2016: Journal of Molecular Biology
Nerea Alonso, Miquel Torrent-Sucarrat, Iosune Arrastia, Ana Arrieta, Fernando P Cossío
The N-demethylation reactions of N,N,N-trimethylpropan-1-ammonium and N,N-dimethyl-, and N-methylpropan-1-aminium cations in the presence of (AcO)2(imidazole)2(H2O)Fe=O complex have been studied by density functional theory. These transformations are suitable models for the N-demethylation of tri-, di-, and monomethylated lysine residues of histones in the presence of Jumonji-C containing histone demethylases. It has been found that the N-demethylation reaction is stepwise and occurs on triplet and quintet potential energy hypersurfaces...
October 11, 2016: Chemistry: a European Journal
B C Medeiros, A T Fathi, C D DiNardo, D A Pollyea, S M Chan, R Swords
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle...
October 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Valentina Damiano, Giulia Brisotto, Silvia Borgna, Alessandra di Gennaro, Michela Armellin, Tiziana Perin, Michela Guardascione, Roberta Maestro, Manuela Santarosa
Loss of expression of miR-200 family members has been implicated in cellular plasticity, a phenomenon that accounts for epithelial-to-mesenchymal transition (EMT) and stem-like features of many carcinomas and is considered a major cause of tumor aggressiveness and drug resistance. Nevertheless, the mechanisms of miR-200 downregulation in breast cancer are still largely unknown. Here we show that miR-200c expression inversely correlates with miR-200c/miR-141 locus methylation in triple-negative breast tumors (TNBC)...
September 22, 2016: Genes, Chromosomes & Cancer
Hesbon Z Amenya, Chiharu Tohyama, Seiichiroh Ohsako
The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1)...
October 7, 2016: Scientific Reports
Megan Breski, Debasis Dey, Sara Obringer, Babu Sudhamalla, Kabirul Islam
Oxidative C-H hydroxylation of methyl groups, followed by their removal from DNA, RNA or histones, is an epigenetic process critical to transcriptional reprogramming and cell fate determination. This reaction is catalyzed by Fe(II)-dependent dioxygenases using the essential metabolite 2-ketoglutarate (2KG) as a cofactor. Given that the human genome encodes for more than 60 2KG-dependent dioxygenases, assigning their individual functions remains a significant challenge. Here we describe a protein-ligand interface engineering approach to break the biochemical degeneracy of these enzymes...
October 6, 2016: Journal of the American Chemical Society
Yuhua Wang, Xueyi Xue, Jian-Kang Zhu, Juan Dong
DNA methylation and histone modifications interplay to modulate gene expression in biological organisms. The histone demethylase IBM1 suppresses DNA methylation and gene silencing, primarily by targeting genic regions in the Arabidopsis genome. The chromatin regulator EMD2 is also required for prevention of genic DNA methylation because it maintains IBM1 expression by promoting IBM1 mRNA distal polyadenylation. Loss-of-function ibm1 and edm2 mutant plants display a wide range of developmental defects, but little is known about what developmentally important genes are regulated by IBM1 and EDM2...
October 3, 2016: Development
Ilkka Kronholm, Hanna Johannesson, Tarmo Ketola
Phenotypic plasticity is the ability of a genotype to produce different phenotypes under different environmental or developmental conditions. Phenotypic plasticity is an ubiquitous feature of living organisms and is typically based on variable patterns of gene expression. However, the mechanisms by which gene expression is influenced and regulated during plastic responses are poorly understood in most organisms. While modifications to DNA and histone proteins have been implicated as likely candidates for generating and regulating phenotypic plasticity, specific details of each modification and its mode of operation have remained largely unknown...
September 30, 2016: G3: Genes—Genomes—Genetics
Seiichiro Kizaki, Tingting Zou, Yue Li, Yong-Woon Han, Yuki Suzuki, Yoshie Harada, Hiroshi Sugiyama
Tet (ten-eleven translocation) family proteins oxidize 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxycytosine (caC), and are suggested to be involved in the active DNA demethylation pathway. In this study, we reconstituted positioned mononucleosomes using CpG-methylated 382 bp DNA containing the Widom 601 sequence and recombinant histone octamer, and subjected the nucleosome to treatment with Tet1 protein. The sites of oxidized methylcytosine were identified by bisulfite sequencing...
September 30, 2016: Chemistry: a European Journal
Kaishan Ye, Shuanke Wang, Jing Wang, Hua Han, Bing Ma, Yong Yang
ARHI is an imprinted tumor suppressor gene and its methylation suppresses ARHI transcription levels to cause the development and progression of malignant tumors. Zebularine exerts demethylation function for tumor suppressor genes. Our study aims to investigate the effect and mechanism of action of zebularine on the epigenetic modification of the ARHI gene, and whether this effect may modulate the viability and apoptosis of human osteosarcoma cells. We found that zebularine inhibited the viability and promoted apoptosis in osteosarcoma cells...
September 29, 2016: Cancer Science
Andrew D King, Kevin Huang, Liudmilla Rubbi, Shuo Liu, Cun-Yu Wang, Yinsheng Wang, Matteo Pellegrini, Guoping Fan
DNA methylation is one of a number of modes of epigenetic gene regulation. Here, we profile the DNA methylome, transcriptome, and global occupancy of histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac) in a series of mouse embryonic stem cells (mESCs) with varying DNA methylation levels to study the effects of DNA methylation on deposition of histone modifications. We find that genome-wide DNA demethylation alters occupancy of histone modifications at both promoters and enhancers. This is reversed upon remethylation by Dnmt expression...
September 27, 2016: Cell Reports
Jing Shen, Shengru Wu, Wei Guo, Saisai Liang, Xueyuan Li, Xiaojun Yang
Inflammatory response which can be mediated by inflammatory genes, can be induced by pathogenic microorganisms, be associated with enteric diseases and the loss of growth performance in broilers. The understanding of epigenetic regulation of inflammatory genes could help explain the response to infection of microorganisms and inhibit the reaction of inflammation in broilers. This study investigated the effect of histone acetylation by histone deacetylases (HDAC) inhibitors trichostain A (TSA) and DNA methylation by demethylation agent 5-Aza-2'-deoxycytidine (AZA) and methyl donor methionine (Met) and folic acid (FA) on the expression of pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) from healthy broilers...
September 18, 2016: Immunobiology
Sumana Chakravarty, Priya Jhelum, Unis Ahmad Bhat, Wenson D Rajan, Swati Maitra, Salil S Pathak, Anant B Patel, Arvind Kumar
Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. Therapeutic interventions to minimize ischemia-induced neural damage are limited due to poor understanding of molecular mechanisms mediating complex pathophysiology in stroke. Recently, epigenetic mechanisms mostly histone lysine (K) acetylation and deacetylation have been implicated in ischemic brain damage and have expanded the dimensions of potential therapeutic intervention to the systemic/ local administration of histone deacetylase inhibitors...
September 21, 2016: Biochimica et Biophysica Acta
Angelo Amabile, Alessandro Migliara, Paola Capasso, Mauro Biffi, Davide Cittaro, Luigi Naldini, Angelo Lombardo
Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. Here, we repurpose the endogenous retroviruses' silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. This was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo DNA methylation, thus ensuring long-term memory of the repressive epigenetic state...
September 22, 2016: Cell
Eunsohl Lee, Jingcheng Wang, Kenji Yumoto, Younghun Jung, Frank C Cackowski, Ann M Decker, Yan Li, Renny T Franceschi, Kenneth J Pienta, Russell S Taichman
Cancer metastasis is a multistep process associated with the induction of an epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Although significant progress has been made in understanding the molecular mechanisms regulating EMT and the CSC phenotype, little is known of how these processes are regulated by epigenetics. Here we demonstrate that reduced expression of DNA methyltransferase 1 (DNMT1) plays an important role in the induction of EMT and the CSC phenotype by prostate cancer (PCa) cells, with enhanced tumorigenesis and metastasis...
September 2016: Neoplasia: An International Journal for Oncology Research
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