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Histone Acetyltransferases (histone + acetyltransferase)

Distribution by Scientific Domains
Life Sciences58%
Medical Sciences25%
Chemistry16%

Terms modified by Histone Acetyltransferases

  • histone acetyltransferase activity
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    Selected Abstracts

    Synthesis of Benzamides Related to Anacardic Acid and Their Histone Acetyltransferase (HAT) Inhibitory Activities

    CHEMMEDCHEM, Issue 9 2008

    Abstract A group of benzamides related to anacardic acid amide CTPB with alkyl chains of defined length were prepared by a five-step sequence starting from 2,6-dihydroxybenzoic acid, and their activities were compared with those reported for the HAT inhibitor anacardic acid (AA). The subset of 4-cyano-3-trifluoromethylphenylbenzamides with shorter chains exhibited activities similar to that of AA, as they behaved as human p300 inhibitors, induced a decrease in histone acetylation levels in immortalized HEK cells, and counteracted the action of the HDAC inhibitor SAHA in MCF7 breast cancer cells. Moreover, an analogue with the shortest alkyl chain induced significant apoptosis at 50,,M in U937 leukemia cells. [source]

    RBP2 is an MRG15 complex component and down-regulates intragenic histone H3 lysine 4 methylation

    GENES TO CELLS, Issue 6 2007
    Tomohiro Hayakawa
    MRG15 is a conserved chromodomain protein that associates with histone deacetylases (HDACs) and Tip60-containing histone acetyltransferase (HAT) complexes. Here we further characterize MRG15-containing complexes and show a functional link between MRG15 and histone H3K4 demethylase activity in mammalian cells. MRG15 was predominantly localized to discrete nuclear subdomains enriched for Ser2 -phosphorylated RNA polymerase II, suggesting it is involved specifically with active transcription. Protein analysis of the MRG15-containing complexes led to the identification of RBP2, a JmjC domain-containing protein. Remarkably, over-expression of RBP2 greatly reduced the H3K4 methylation in culture human cells in vivo, and recombinant RBP2 efficiently removed H3K4 methylation of histone tails in vitro. Knockdown of RBP2 resulted in increased H3K4 methylation levels within transcribed regions of active genes. Our findings demonstrate that RBP2 associated with MRG15 complex to maintain reduced H3K4 methylation at transcribed regions, which may ensure the transcriptional elongation state. [source]

    Emerging Role of Epigenetics in the Actions of Alcohol

    ALCOHOLISM, Issue 9 2008
    Shivendra D. Shukla
    This review deals with the recent developments on the epigenetic effects of ethanol. A large body of data have come from studies in liver and in neuronal systems and involve post-translational modifications in histones and methylations in DNA. Ethanol causes site selective acetylation, methylation, and phosphorylation in histone. With respect to methylations the methyl group donating system involving S-adenosyl methionine appears to play a central role. There is contrasting effect of acetylation versus methylation on the same site of histone, as it relates to the transcriptional activation. Epigenetic memory also appears to correlate with liver pathology and Mallory body formation. Experimental evidence supports transcriptional regulation of genes in the CNS by DNA methylations. These studies are contributing towards a better understanding of a novel epigenetic regulation of gene expression in the context of alcohol. The critical steps and the enzymes (e.g., histone acetyltransferase, histone deacetylase, DNA methyltransferase) responsible for the epigenetic modifications are prime targets for intense investigation. The emerging data are also beginning to offer novel insight towards defining the molecular actions of ethanol and may contribute to potential therapeutic targets at the nucleosomal level. These epigenetic studies have opened up a new avenue of investigation in the alcohol field. [source]

    Montelukast inhibits tumour necrosis factor-,-mediated interleukin-8 expression through inhibition of nuclear factor-,B p65-associated histone acetyltransferase activity

    CLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2008
    F. Tahan
    Summary Background Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist possessing some anti-inflammatory effects although the molecular mechanism of these anti-inflammatory effects is unknown. In this study, we aimed to investigate the effect of montelukast on nuclear factor (NF)-,B-associated histone acetylation activity in phorbol myristate acetate (PMA)-differentiated U937 cells. Methods We examined the inhibitory effects of montelukast on TNF-,-induced IL-8 production in PMA-differentiated U-937 cells. U-937 cells were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages. Macrophages were then exposed to TNF-, (10 ng/mL) in the presence or absence of montelukast (0.01,10 ,m) for 24 h. After this time, the concentration of IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The effect of signalling pathways on TNF-,-induced IL-8 release was examined pharmacologically using selective NF-,B/IKK2 (AS602868, 3 ,m), (PD98059, 10 ,m) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 ,m) inhibitors. NF-,B DNA binding activity was measured by a DNA-binding ELISA-based assay. NF-,B-p65-associated histone acetyltransferase (HAT) activity was measured by immunoprecipitation linked to commercial flourescent HAT. Results TNF-,-induced IL-8 release was suppressed by an NF-,B inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a concentration-dependent inhibition of TNF-,-induced IL-8 release and mRNA expression that reached a plateau at 0.1 ,m without affecting cell viability. Montelukast did not affect NF-,B p65 activation as measured by DNA binding but suppressed NF-,B p65-associated HAT activity. Conclusion Montelukast inhibits TNF-,-stimulated IL-8 expression through changes in NF-,B p65-associated HAT activity. Drugs targeting these enzymes may enhance the anti-inflammatory actions of montelukast. [source]

    Role of histone and transcription factor acetylation in diabetes pathogenesis

    DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2005
    Steven G. Gray
    Abstract Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed $100 billion annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The ,Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications. Copyright © 2005 John Wiley & Sons, Ltd. [source]

    The regulation of HIV-1 transcription: Molecular targets for chemotherapeutic intervention

    MEDICINAL RESEARCH REVIEWS, Issue 5 2006
    Miguel Stevens
    Abstract The regulation of transcription of the human immunodeficiency virus (HIV) is a complex event that requires the cooperative action of both viral and cellular components. In latently infected resting CD4+ T cells HIV-1 transcription seems to be repressed by deacetylation events mediated by histone deacetylases (HDACs). Upon reactivation of HIV-1 from latency, HDACs are displaced in response to the recruitment of histone acetyltransferases (HATs) by NF-,B or the viral transcriptional activator Tat and result in multiple acetylation events. Following chromatin remodeling of the viral promoter region, transcription is initiated and leads to the formation of the TAR element. The complex of Tat with p-TEFb then binds the loop structures of TAR RNA thereby positioning CDK9 to phosphorylate the cellular RNA polymerase II. The Tat-TAR-dependent phosphorylation of RNA polymerase II plays an important role in transcriptional elongation as well as in other post-transcriptional events. As such, targeting of Tat protein (and/or cellular cofactors) provide an interesting perspective for therapeutic intervention in the HIV replicative cycle and may afford lifetime control of the HIV infection. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 595,625, 2006 [source]

    In vitro specificities of Arabidopsis co-activator histone acetyltransferases: implications for histone hyperacetylation in gene activation

    THE PLANT JOURNAL, Issue 4 2007
    Keith W. Earley
    Summary In genetic hybrids displaying nucleolar dominance, acetylation of lysines 5, 8, 12 and 16 of histone H4 (H4K5, H4K8, H4K12, H4K16) and acetylation of histone H3 on lysines 9 and 14 (H3K9, H3K14) occurs at the promoters of active ribosomal RNA (rRNA) genes, whereas silenced rRNA genes are deacetylated. Likewise, histone hyperacetylation correlates with the active state of transgenes and of endogenous plant genes involved in physiological processes, including cold tolerance, light-responsiveness and flowering. To investigate histone hyperacetylation dynamics we used sodium butyrate, a histone deacetylase inhibitor known to switch silent rRNA genes on, in order to enrich the pool of acetylated histones. Mass spectrometric analyses revealed unique mono- (K16Ac), di- (K12Ac, K16Ac), tri- (K8Ac, K12Ac, K16Ac), and tetra-acetylated (K5Ac, K8Ac, K12Ac, K16Ac) histone H4 isoforms, suggesting that H4 hyperacetylation occurs in a processive fashion, beginning with lysine 16 and ending with lysine 5. Using a combination of molecular and mass spectrometric assays we then determined the specificities of seven of the nine functional co-activator type histone acetyltransferases (HATs) in Arabidopsis thaliana: specifically HATs of the CBP (HAC1, HAC5, HAC12), GNAT (HAG1, HAG2), and MYST families (HAM1, HAM2). Specific HATs acetylate histone H4K5 (HAM1, HAM2), H4K12 (HAG2), and H3K14 (HAG1), suggesting that acetylation of these lysines may have special regulatory significance. Other acetylation events, including histone H3K9 acetylation, are likely to result from the activities of the broad-specificity HAC1, HAC5, and HAC12 histone acetyltransferases. [source]

    MYST family histone acetyltransferases take center stage in stem cells and development

    BIOESSAYS, Issue 10 2009
    Anne K. Voss
    Abstract Acetylation of histones is an essential element regulating chromatin structure and transcription. MYST (Moz, Ybf2/Sas3, Sas2, Tip60) proteins form the largest family of histone acetyltransferases and are present in all eukaryotes. Surprisingly, until recently this protein family was poorly studied. However, in the last few years there has been a substantial increase in interest in the MYST proteins and a number of key studies have shown that these chromatin modifiers are required for a diverse range of cellular processes, both in health and disease. Translocations affecting MYST histone acetyltransferases can lead to leukemia and solid tumors. Some members of the MYST family are required for the development and self-renewal of stem cell populations; other members are essential for the prevention of inappropriate heterochromatin spreading and for the maintenance of adequate levels of gene expression. In this review we discuss the function of MYST proteins in vivo. [source]

    Reversible acetylation of chromatin: Implication in regulation of gene expression, disease and therapeutics

    BIOTECHNOLOGY JOURNAL, Issue 3 2009
    Ruthrotha B. Selvi
    Abstract The eukaryotic genome is a highly dynamic nucleoprotein complex that is comprised of DNA, histones, nonhistone proteins and RNA, and is termed as chromatin. The dynamicity of the chromatin is responsible for the regulation of all the DNA-templated phenomena in the cell. Several factors, including the nonhistone chromatin components, ATP-dependent remodeling factors and the chromatin-modifying enzymes, mediate the combinatorial post-translational modifications that control the chromatin fluidity and, thereby, the cellular functions. Among these modifications, reversible acetylation plays a central role in the highly orchestrated network. The enzymes responsible for the reversible acetylation, the histone acetyltransferases (HATs) and histone deacetylases (HDACs), not only act on histone substrates but also on nonhistone proteins. Dysfunction of the HATs/HDACs is associated with various diseases like cancer, diabetes, asthma, cardiac hypertrophy, retroviral pathogenesis and neurodegenerative disorders. Therefore, modulation of these enzymes is being considered as an important therapeutic strategy. Although substantial progress has been made in the area of HDAC inhibitors, we have focused this review on the HATs and their small-molecule modulators in the context of disease and therapeutics. Recent discoveries from different groups have established the involvement of HAT function in various diseases. Furthermore, several new classes of HAT modulators have been identified and their biological activities have also been reported. The scaffold of these small molecules can be used for the design and synthesis of better and efficient modulators with superior therapeutic efficacy. [source]