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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
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
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, 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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18 MeSH Terms
Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation.
Li Y, Yokota T, Gama V, Yoshida T, Gomez JA, Ishikawa K, Sasaguri H, Cohen HY, Sinclair DA, Mizusawa H, Matsuyama S
(2007) Cell Death Differ 14: 2058-67
MeSH Terms: Acetylation, Animals, Antigens, Nuclear, Caspases, Cell Death, Cell Line, Cyclic AMP Response Element-Binding Protein, Cytoprotection, DNA Fragmentation, DNA-Binding Proteins, Histone Acetyltransferases, Humans, Ku Autoantigen, Mutant Proteins, Peptides, Protein Binding, Protein Conformation, Rats, Rats, Sprague-Dawley, Resveratrol, Stilbenes, Vacuoles, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases.
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23 MeSH Terms
CCAAT displacement protein regulates nuclear factor-kappa beta-mediated chemokine transcription in melanoma cells.
Ueda Y, Su Y, Richmond A
(2007) Melanoma Res 17: 91-103
MeSH Terms: Apoptosis, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, Chemokines, Gene Expression Regulation, Neoplastic, Histone Acetyltransferases, Homeodomain Proteins, Humans, Melanoma, NF-kappa B, Neoplasm Metastasis, Nuclear Proteins, Promoter Regions, Genetic, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Repressor Proteins, Transcription Factors, Transcription, Genetic, p300-CBP Transcription Factors
Show Abstract · Added May 31, 2013
Members of the nuclear factor-kappa beta (NF-kappaB) family maintain cellular homeostasis by enhancing the transcription of genes involved in inflammation, immune response, cell proliferation, and apoptosis. Melanoma tumor cells often express inflammatory mediators through enhanced activation of NF-kappaB. The NF-kappaB activation appears to result from the enhancer formation including NF-kappaB and lysine acetyl transferases such as p300, CREB (cyclic AMP-responsive element binding protein)-binding protein (CBP), and/or p300/CBP associating factor (PCAF). We observed that proteins expressed by Hs294T metastatic melanoma cells are highly acetylated compared with normal melanocytes, and dominant-negative PCAF reduced the basal and tumor necrosis factor-alpha-stimulated transcriptional activity of NF-kappaB. The promoter activity of NF-kappaB-regulated chemokines was also reduced by the expression of dominant-negative PCAF. The promoters of these chemokines contain a CCAAT displacement protein (CDP)-binding site near the NF-kappaB element. compared with vector-transduced cells, in CDP-transduced Hs294T cells: (i) over-expressed CDP bound efficiently to PCAF, (ii) tumor necrosis factor-alpha-stimulated chemokine expression and NF-kappaB-mediated transcription were reduced, and (iii) the binding of CBP to Rel A was reduced. These data suggest that CDP inhibits cytokine-induced NF-kappaB-regulated chemokine transcription. This study contributes to our understanding of the role of CDP in an enhanceosome of NF-kappaB-mediated chemokine transcription in human melanoma cells.
2 Communities
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20 MeSH Terms
ErbB receptor signaling and therapeutic resistance to aromatase inhibitors.
Shin I, Miller T, Arteaga CL
(2006) Clin Cancer Res 12: 1008s-1012s
MeSH Terms: Acetyltransferases, Androstenedione, Aromatase Inhibitors, Breast Neoplasms, Carrier Proteins, Cell Line, Tumor, Corticosterone, Drug Resistance, Neoplasm, Female, Histone Acetyltransferases, Humans, Letrozole, Nitriles, Nuclear Receptor Coactivator 3, Oncogene Proteins, Promoter Regions, Genetic, Receptor, ErbB-2, Receptors, Estrogen, Signal Transduction, Trans-Activators, Transcriptional Activation, Triazoles
Show Abstract · Added March 5, 2014
We have investigated the effect of HER-2 overexpression on resistance to the aromatase inhibitor letrozole in MCF-7 breast cancer cells stably expressing cellular aromatase (MCF-7/CA). MCF-7/CA cells overexpressing HER-2 showed a >2-fold increase in estrogen receptor (ER)-mediated transcriptional reporter activity upon treatment with androstenedione compared with vector-only control MCF-7/CA cells. Co-treatment with letrozole did not abrogate androstenedione-induced transcription and cell proliferation in HER-2-overexpressing cells. Chromatin immunoprecipitation assays using cross-linked protein-DNA from MCF-7/CA/HER-2 cells indicated ligand-independent association of the ERalpha coactivators AIB-1 and CBP to the promoter region of the estrogen-responsive pS2 gene. Upon treatment with androstenedione, there were increased associations of AIB1 and CBP with the pS2 promoter in the HER-2-overexpressing compared with control MCF-7/CA cells. These results suggest that ligand-independent recruitment of coactivator complexes to estrogen-responsive promoters as a result of HER-2 overexpression may play a role in the development of letrozole resistance.
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22 MeSH Terms
The proteasome regulatory particle alters the SAGA coactivator to enhance its interactions with transcriptional activators.
Lee D, Ezhkova E, Li B, Pattenden SG, Tansey WP, Workman JL
(2005) Cell 123: 423-36
MeSH Terms: Acetylation, Adenosine Triphosphatases, Gene Expression Regulation, Fungal, Histone Acetyltransferases, Histones, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factors
Show Abstract · Added March 10, 2014
Promoter recruitment of the Saccharomyces cerevisiae SAGA histone acetyltransferase complex is required for RNA polymerase II-dependent transcription of several genes. SAGA is targeted to promoters through interactions with sequence-specific DNA binding transcriptional activators and facilitates preinitiation-complex assembly and transcription. Here, we show that the 19S proteasome regulatory particle (19S RP) alters SAGA to stimulate its interaction with transcriptional activators. The ATPase components of the 19S RP are required for stimulation of SAGA/activator interactions and enhance SAGA recruitment to promoters. Proteasomal ATPases genetically interact with SAGA, and their inhibition reduces global histone H3 acetylation levels and SAGA recruitment to target promoters in vivo. These results indicate that the 19S RP modulates SAGA complex using its ATPase components, thereby facilitating subsequent transcription events at promoters.
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10 MeSH Terms
Translating the histone code into leukemia.
Linggi BE, Brandt SJ, Sun ZW, Hiebert SW
(2005) J Cell Biochem 96: 938-50
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Chromatin, Chromosomes, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Histone Acetyltransferases, Histone Deacetylases, Histones, Humans, Leukemia, Models, Biological, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-6, Recombinant Fusion Proteins, Translocation, Genetic
Show Abstract · Added March 5, 2014
The "histone code" is comprised of the covalent modifications of histone tails that function to regulate gene transcription. The post-translational modifications that occur in histones within the regulatory regions of genes include acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation. These modifications serve to alter chromatin structure and accessibility, and to act as docking sites for transcription factors or other histone modifying enzymes. Several of the factors that are disrupted by chromosomal translocations associated with hematological malignancies can alter the histone code in a gene-specific manner. Here, we discuss how the histone code may be disrupted by chromosomal translocations, either directly by altering the activity of histone modifying enzymes, or indirectly by recruitment of this type of enzyme by oncogenic transcription factors. These alterations in the histone code may alter gene expression pattern to set the stage for leukemogenesis.
2005 Wiley-Liss, Inc.
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19 MeSH Terms
Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1.
Li Y, Choi M, Cavey G, Daugherty J, Suino K, Kovach A, Bingham NC, Kliewer SA, Xu HE
(2005) Mol Cell 17: 491-502
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, Crystallography, DNA-Binding Proteins, Histone Acetyltransferases, Homeodomain Proteins, Hydrogen Bonding, Ligands, Mice, Molecular Sequence Data, Mutation, Nuclear Receptor Coactivator 1, Phospholipids, Protein Conformation, Receptors, Cytoplasmic and Nuclear, Sequence Homology, Amino Acid, Steroidogenic Factor 1, Transcription Factors, Transcription, Genetic
Show Abstract · Added October 13, 2015
The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 angstroms crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket (approximately 1600 angstroms3), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and endocrine development and function.
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20 MeSH Terms
Cluster analysis of mass spectrometry data reveals a novel component of SAGA.
Powell DW, Weaver CM, Jennings JL, McAfee KJ, He Y, Weil PA, Link AJ
(2004) Mol Cell Biol 24: 7249-59
MeSH Terms: Acetyltransferases, Cluster Analysis, Gene Expression Regulation, Fungal, Histone Acetyltransferases, Mass Spectrometry, Multienzyme Complexes, Oligonucleotide Array Sequence Analysis, Open Reading Frames, Protein Subunits, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factor TFIID, Transcription Factors, Transcription, Genetic
Show Abstract · Added June 14, 2013
The SAGA histone acetyltransferase and TFIID complexes play key roles in eukaryotic transcription. Using hierarchical cluster analysis of mass spectrometry data to identify proteins that copurify with components of the budding yeast TFIID transcription complex, we discovered that an uncharacterized protein corresponding to the YPL047W open reading frame significantly associated with shared components of the TFIID and SAGA complexes. Using mass spectrometry and biochemical assays, we show that YPL047W (SGF11, 11-kDa SAGA-associated factor) is an integral subunit of SAGA. However, SGF11 does not appear to play a role in SAGA-mediated histone acetylation. DNA microarray analysis showed that SGF11 mediates transcription of a subset of SAGA-dependent genes, as well as SAGA-independent genes. SAGA purified from a sgf11 Delta deletion strain has reduced amounts of Ubp8p, and a ubp8 Delta deletion strain shows changes in transcription similar to those seen with the sgf11 Delta deletion strain. Together, these data show that Sgf11p is a novel component of the yeast SAGA complex and that SGF11 regulates transcription of a subset of SAGA-regulated genes. Our data suggest that the role of SGF11 in transcription is independent of SAGA's histone acetyltransferase activity but may involve Ubp8p recruitment to or stabilization in SAGA.
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14 MeSH Terms