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Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice.
Filgueiras LR, Brandt SL, Ramalho TR, Jancar S, Serezani CH
(2017) J Diabetes Complications 31: 334-339
MeSH Terms: Acetylation, Animals, Bone Marrow Cells, Cells, Cultured, Diabetes Mellitus, Type 1, Enzyme Inhibitors, Epigenesis, Genetic, Gene Expression Regulation, Glucose, Histone Acetyltransferases, Histone Deacetylases, Histones, Macrophages, Macrophages, Peritoneal, Male, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, Osmolar Concentration, Promoter Regions, Genetic, Protein Processing, Post-Translational, STAT1 Transcription Factor, Streptozocin
Show Abstract · Added May 4, 2017
AIMS - To investigate the hypothesis that alteration in histone acetylation/deacetylation triggers aberrant STAT1/MyD88 expression in macrophages from diabetics. Increased STAT1/MyD88 expression is correlated with sterile inflammation in type 1 diabetic (T1D) mice.
METHODS - To induce diabetes, we injected low-doses of streptozotocin in C57BL/6 mice. Peritoneal or bone marrow-differentiated macrophages were cultured in 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone H3 in MyD88 and STAT1 promoter regions. Macrophages from diabetic mice were treated with the histone acetyltransferase inhibitor anacardic acid (AA), followed by determination of mRNA expression by qPCR.
RESULTS - Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Stat1/Myd88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression.
CONCLUSIONS/INTERPRETATION - These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.
Copyright © 2016 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma.
Marien E, Meister M, Muley T, Gomez Del Pulgar T, Derua R, Spraggins JM, Van de Plas R, Vanderhoydonc F, Machiels J, Binda MM, Dehairs J, Willette-Brown J, Hu Y, Dienemann H, Thomas M, Schnabel PA, Caprioli RM, Lacal JC, Waelkens E, Swinnen JV
(2016) Oncotarget 7: 12582-97
MeSH Terms: Acetyltransferases, Animals, Carcinoma, Squamous Cell, Fatty Acid Elongases, Heterografts, Humans, Lung Neoplasms, Mice, Phospholipids
Show Abstract · Added February 22, 2016
Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.
1 Communities
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9 MeSH Terms
Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach.
Suarez G, Romero-Gallo J, Piazuelo MB, Wang G, Maier RJ, Forsberg LS, Azadi P, Gomez MA, Correa P, Peek RM
(2015) Cancer Res 75: 1749-59
MeSH Terms: Acetylation, Acetyltransferases, Adenocarcinoma, Aged, Amidohydrolases, Animals, Bacterial Proteins, Cell Transformation, Neoplastic, Cells, Cultured, Female, Gastritis, Gene Silencing, Gerbillinae, HEK293 Cells, Helicobacter pylori, Host-Pathogen Interactions, Humans, Male, Middle Aged, Nod1 Signaling Adaptor Protein, Organisms, Genetically Modified, Peptidoglycan, Stomach Neoplasms
Show Abstract · Added February 5, 2016
Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan into host cells. NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure. We previously demonstrated that the H. pylori cag(+) strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Coculture of H. pylori strain 7.13 or its pgdA(-) isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA(-) mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, preactivation of NOD1 before bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared with noncancer samples harvested from the same patients. These results indicate that peptidoglycan deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.
©2015 American Association for Cancer Research.
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23 MeSH Terms
Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.
Smith CE, Follis JL, Nettleton JA, Foy M, Wu JH, Ma Y, Tanaka T, Manichakul AW, Wu H, Chu AY, Steffen LM, Fornage M, Mozaffarian D, Kabagambe EK, Ferruci L, Chen YD, Rich SS, Djoussé L, Ridker PM, Tang W, McKnight B, Tsai MY, Bandinelli S, Rotter JI, Hu FB, Chasman DI, Psaty BM, Arnett DK, King IB, Sun Q, Wang L, Lumley T, Chiuve SE, Siscovick DS, Ordovás JM, Lemaitre RN
(2015) Mol Nutr Food Res 59: 1373-83
MeSH Terms: Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acid Elongases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added April 23, 2015
SCOPE - Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.
METHODS AND RESULTS - We conducted meta-analyses (N = 11 668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.
CONCLUSION - Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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17 MeSH Terms
Pyruvate formate-lyase interacts directly with the formate channel FocA to regulate formate translocation.
Doberenz C, Zorn M, Falke D, Nannemann D, Hunger D, Beyer L, Ihling CH, Meiler J, Sinz A, Sawers RG
(2014) J Mol Biol 426: 2827-39
MeSH Terms: Acetyltransferases, Chromatography, Liquid, Cross-Linking Reagents, Escherichia coli, Escherichia coli Proteins, Formates, Immunoprecipitation, Membrane Transport Proteins, Models, Molecular, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Two-Hybrid System Techniques
Show Abstract · Added January 24, 2015
The FNT (formate-nitrite transporters) form a superfamily of pentameric membrane channels that translocate monovalent anions across biological membranes. FocA (formate channel A) translocates formate bidirectionally but the mechanism underlying how translocation of formate is controlled and what governs substrate specificity remains unclear. Here we demonstrate that the normally soluble dimeric enzyme pyruvate formate-lyase (PflB), which is responsible for intracellular formate generation in enterobacteria and other microbes, interacts specifically with FocA. Association of PflB with the cytoplasmic membrane was shown to be FocA dependent and purified, Strep-tagged FocA specifically retrieved PflB from Escherichia coli crude extracts. Using a bacterial two-hybrid system, it could be shown that the N-terminus of FocA and the central domain of PflB were involved in the interaction. This finding was confirmed by chemical cross-linking experiments. Using constraints imposed by the amino acid residues identified in the cross-linking study, we provide for the first time a model for the FocA-PflB complex. The model suggests that the N-terminus of FocA is important for interaction with PflB. An in vivo assay developed to monitor changes in formate levels in the cytoplasm revealed the importance of the interaction with PflB for optimal translocation of formate by FocA. This system represents a paradigm for the control of activity of FNT channel proteins.
Copyright © 2014 Elsevier Ltd. All rights reserved.
1 Communities
1 Members
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11 MeSH Terms
Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4.
Nagarajan P, Ge Z, Sirbu B, Doughty C, Agudelo Garcia PA, Schlederer M, Annunziato AT, Cortez D, Kenner L, Parthun MR
(2013) PLoS Genet 9: e1003518
MeSH Terms: Acetylation, Animals, Cell Proliferation, Cell Survival, Chromatin Assembly and Disassembly, DNA Replication, Embryonic Development, Fibroblasts, Genomic Instability, Histone Acetyltransferases, Histones, Humans, Jumonji Domain-Containing Histone Demethylases, Mice, Mice, Knockout
Show Abstract · Added March 7, 2014
Histone acetyltransferase 1 is an evolutionarily conserved type B histone acetyltransferase that is thought to be responsible for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 during chromatin assembly. To understand the function of this enzyme in a complex organism, we have constructed a conditional mouse knockout model of Hat1. Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality. The lungs of embryos and pups genetically deficient in Hat1 were much less mature upon histological evaluation. The neonatal lethality is due to severe defects in lung development that result in less aeration and respiratory distress. Many of the Hat1(-/-) neonates also display significant craniofacial defects with abnormalities in the bones of the skull and jaw. Hat1(-/-) mouse embryonic fibroblasts (MEFs) are defective in cell proliferation and are sensitive to DNA damaging agents. In addition, the Hat1(-/-) MEFs display a marked increase in genome instability. Analysis of histone dynamics at sites of replication-coupled chromatin assembly demonstrates that Hat1 is not only responsible for the acetylation of newly synthesized histone H4 but is also required to maintain the acetylation of histone H3 on lysines 9, 18, and 27 during replication-coupled chromatin assembly.
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15 MeSH Terms
The evolution of a superbug: how Staphylococcus aureus overcomes its unique susceptibility to polyamines.
Anzaldi LL, Skaar EP
(2011) Mol Microbiol 82: 1-3
MeSH Terms: Acetyltransferases, Bacterial Proteins, Spermidine, Spermine, Staphylococcus aureus
Show Abstract · Added February 11, 2016
Polyamines are ubiquitous compounds thought to be synthesized by and required for all life. The manuscript published in this issue by Joshi and colleagues upsets this dogma by identifying several bacterial species that do not make polyamines, and in some cases do not require polyamines for growth. One such species is the significant human pathogen Staphylococcus aureus, which is shown to be uniquely sensitive to polyamines. By unravelling the mechanisms of staphylococcal polyamine toxicity and tolerance, Joshi et al. (2011) provide insights into how the most virulent strains of S. aureus have evolved to be more fit during infection.
© 2011 Blackwell Publishing Ltd.
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5 MeSH Terms
Methods to evaluate alterations in polyamine metabolism caused by Helicobacter pylori infection.
Gobert AP, Chaturvedi R, Wilson KT
(2011) Methods Mol Biol 720: 409-25
MeSH Terms: Acetyltransferases, Animals, Apoptosis, Arginase, Arsenicals, Biochemistry, Cells, Cultured, Enzyme Assays, Helicobacter Infections, Helicobacter pylori, Humans, Immunoblotting, Luciferases, Macrophages, Mice, Nitrogen Dioxide, Ornithine Decarboxylase, Oxidoreductases Acting on CH-NH Group Donors, Polyamines, Promoter Regions, Genetic, RNA, Messenger, Transfection
Show Abstract · Added March 5, 2014
Helicobacter pylori is a Gram-negative bacteria that infects the human stomach of half of the world's -population. Colonization is followed by infiltration of the gastric mucosa by lymphocytes and myeloid cells. These cells are activated by various bacterial factors, causing them to produce immune/inflammatory mediators, including reactive nitrogen species and polyamines that contribute to cellular damage and the pathogenesis of H. pylori-associated gastric cancer. In vitro experiments have revealed that H. pylori induces macrophage polyamine production by upregulation of the arginase 2/ornithine decarboxylase (ODC) metabolic pathway and enhances hydrogen peroxide synthesis through the activity of spermidine oxidase (SMO). In this chapter, we present a survey of the methods used to analyze the induction and the role of the enzymes related to polyamine metabolism, i.e., arginase, ODC, and SMO in H. pylori-infected macrophages.
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22 MeSH Terms
T-bet dependent removal of Sin3A-histone deacetylase complexes at the Ifng locus drives Th1 differentiation.
Chang S, Collins PL, Aune TM
(2008) J Immunol 181: 8372-81
MeSH Terms: Acetylation, Animals, Cell Differentiation, Cell Proliferation, Cells, Cultured, Histone Acetyltransferases, Histone Deacetylase Inhibitors, Histone Deacetylases, Histones, Interferon-gamma, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Protein Transport, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex, T-Box Domain Proteins, Th1 Cells
Show Abstract · Added December 10, 2013
Forming and removing epigenetic histone marks at gene loci are central processes in differentiation. Here, we explored mechanisms establishing long-range H4 acetylation marks at the Ifng locus during Th1 lineage commitment. In Th0 cells, histone deacetylase (HDAC)-Sin3A complexes recruited to the Ifng locus actively prevented accumulation of H4 acetylation marks. Th1 differentiation caused loss of HDAC-Sin3A complexes by T-bet-dependent mechanisms and accumulation of H4 acetylation marks. HDAC-Sin3A complexes were absent from the locus in NOD Th0 cells, obviating the need for Th1 differentiation signals to establish histone marks and Th1 differentiation. Thus, Ifng transcription is actively prevented in Th0 cells via epigenetic mechanisms and epigenetic defects allow unregulated Ifng transcription that may contribute to autoimmunity.
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19 MeSH Terms
Meat intake, heterocyclic amine exposure, and metabolizing enzyme polymorphisms in relation to colorectal polyp risk.
Shin A, Shrubsole MJ, Rice JM, Cai Q, Doll MA, Long J, Smalley WE, Shyr Y, Sinha R, Ness RM, Hein DW, Zheng W
(2008) Cancer Epidemiol Biomarkers Prev 17: 320-9
MeSH Terms: Acetyltransferases, Adult, Aged, Chi-Square Distribution, Colonic Polyps, Colonoscopy, Cytochrome P-450 Enzyme System, Genotype, Humans, Meat, Middle Aged, Phenotype, Polymorphism, Genetic, Receptors, Aryl Hydrocarbon, Risk Factors, Tennessee
Show Abstract · Added March 10, 2014
Most colorectal cancers arise from adenomatous polyps or certain hyperplastic polyps. Only a few studies have investigated potential genetic modifiers of the associations between meat intake and polyp risk, and results are inconsistent. Using data from the Tennessee Colorectal Polyp Study, a large colonoscopy-based study, including 1,002 polyp cases (557 adenoma only, 250 hyperplastic polyp only, 195 both polyps) and 1,493 polyp-free patients, we evaluated the association of colorectal polyp risk with carcinogen exposure from meat and genetic polymorphisms in enzymes involved in heterocyclic amine (HCA) metabolism, including N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP1A2), and aryl hydrocarbon receptor (AhR). Data on intake levels of meats by preparation methods, doneness preferences, and other lifestyle factors were obtained. Fourteen single nucleotide polymorphisms in the AhR, CYP1A2, NAT1, and NAT2 genes were evaluated. No clear association was found for any polymorphisms with polyp risk. However, apparent interactions were found for intake of meat and HCAs with AhR, NAT1, and NAT2 genotypes, and the interactions were statistically significant for the group with both adenomatous and hyperplastic polyps. Dose-response relationships with meat or HCA intake were found only among those with the AhR GA/AA (rs2066853) genotype, NAT1 rapid, or NAT2 rapid/intermediate acetylators but not among those with other genotypes of these genes. This dose-response relationship was more evident among those with both AhR GA/AA and the NAT1 rapid acetylator than those without this genotype combination. These results provide strong evidence for a modifying effect of metabolizing genes on the association of meat intake and HCA exposure with colorectal polyp risk.
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16 MeSH Terms