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  • Topoisomerase IIbeta negatively modulates retinoic acid receptor alpha function: a novel mechanism of retinoic acid resistance. 18212063

    Interactions between retinoic acid (RA) receptor alpha (RARalpha) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In patients with acute promyelocytic leukemia (APL), the RARalpha gene is fused with the promyelocytic leukemia (PML) gene via the t(15;17) translocation, resulting in the expression of a PML/RARalpha fusion protein. Here, we report that topoisomerase II beta (TopoIIbeta) associates with and negatively modulates RARalpha transcriptional activity and that increased levels of and association with TopoIIbeta cause resistance to RA in APL cell lines. Knockdown of TopoIIbeta was able to overcome resistance by permitting RA-induced differentiation and increased RA gene expression. Overexpression of TopoIIbeta in clones from an RA-sensitive cell line conferred resistance by a reduction in RA-induced expression of target genes and differentiation. Chromatin immunoprecipitation assays indicated that TopoIIbeta is bound to an RA response element and that inhibition of TopoIIbeta causes hyperacetylation of histone 3 at lysine 9 and activation of transcription. Our results identify a novel mechanism of resistance in APL and provide further insight to the role of TopoIIbeta in gene regulation and differentiation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-942
    Nombre del producto:
    Anti-acetyl-Histone H3 (Lys9) Antibody

  • Histone exchange activity and its correlation with histone acetylation status in porcine oocytes. 21239526

    In mammalian oocytes, histone H3 and histone H4 (H4) in the chromatin are highly acetylated at the germinal vesicle (GV) stage, and become globally deacetylated after GV breakdown (GVBD). Although nuclear core histones can be exchanged by cytoplasmic free histones in somatic cells, it remains unknown whether this is also the case in mammalian oocytes. In this study, we examined the histone exchange activity in maturing porcine oocytes before and after GVBD, and investigated the correlations between this activity and both the acetylation profile of the H4 N-terminal tail and the global histone acetylation level in the chromatin. We injected Flag-tagged H4 (H4-Flag) mRNA into GV oocytes, and found that the Flag signal was localized to the chromatin. We next injected mRNAs of mutated H4-Flag, which lack all acetylation sites and the whole N-terminal tail, and found that the H4 N-terminal tail and its modification were not necessary for histone incorporation into chromatin. Despite the lack of acetylation sites, the mutated H4-Flag mRNA injection did not decrease the acetylation level on the chromatin, indicating that the histone exchange occurs partially in the GV chromatin. In contrast to GV oocytes, the Flag signal was not detected on the chromatin after the injection of H4-Flag protein into the second meiotic metaphase oocytes. These results suggest that histone exchange activity changes during meiotic maturation in porcine oocytes, and that the acetylation profile of the H4 N-terminal tail has no effect on histone incorporation into chromatin and does not affect the global level of histone acetylation in it.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AP181R
    Nombre del producto:
    Goat Anti-Mouse IgG Antibody, Rhodamine conjugate, Species Adsorbed

  • Regulation of histone H2A.Z expression is mediated by sirtuin 1 in prostate cancer. 24127549

    Histone variants seem to play a major role in gene expression regulation. In prostate cancer, H2A.Z and its acetylated form are implicated in oncogenes' upregulation. SIRT1, which may act either as tumor suppressor or oncogene, reduces H2A.Z levels in cardiomyocytes, via proteasome-mediated degradation, and this mechanism might be impaired in prostate cancer cells due to sirtuin 1 downregulation. Thus, we aimed to characterize the mechanisms underlying H2A.Z and SIRT1 deregulation in prostate carcinogenesis and how they interact. We found that H2AFZ and SIRT1 were up- and downregulated, respectively, at transcript level in primary prostate cancer and high-grade prostatic intraepithelial neoplasia compared to normal prostatic tissues. Induced SIRT1 overexpression in prostate cancer cell lines resulted in almost complete absence of H2A.Z. Inhibition of mTOR had a modest effect on H2A.Z levels, but proteasome inhibition prevented the marked reduction of H2A.Z due to sirtuin 1 overexpression. Prostate cancer cells exposed to epigenetic modifying drugs trichostatin A, alone or combined with 5-aza-2'-deoxycytidine, increased H2AFZ transcript, although with a concomitant decrease in protein levels. Conversely, SIRT1 transcript and protein levels increased after exposure. ChIP revealed an increase of activation marks within the TSS region for both genes. Remarkably, inhibition of sirtuin 1 with nicotinamide, increased H2A.Z levels, whereas activation of sirtuin 1 by resveratrol led to an abrupt decrease in H2A.Z. Finally, protein-ligation assay showed that exposure to epigenetic modifying drugs fostered the interaction between sirtuin 1 and H2A.Z. We concluded that sirtuin 1 and H2A.Z deregulation in prostate cancer are reciprocally related. Epigenetic mechanisms, mostly histone post-translational modifications, are likely involved and impair sirtuin 1-mediated downregulation of H2A.Z via proteasome-mediated degradation. Epigenetic modifying drugs in conjunction with enzymatic modulators are able to restore the normal functions of sirtuin 1 and might constitute relevant tools for targeted therapy of prostate cancer patients.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-409
    Nombre del producto:
    EZ-Magna ChIP™ G - Chromatin Immunoprecipitation Kit

  • Modulation of histone acetylation by [4-(acetylamino)-N-(2-amino-phenyl) benzamide] in HCT-8 colon carcinoma. 12700284

    CI-994 or N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] is an antitumor cytostatic agent currently undergoing clinical trial. Although several changes in cellular metabolism induced by the drug have been characterized, the primary molecular mechanism of its antitumor activity has been previously unknown. Here, we show that CI-994 is a histone deacetylase (HDAC) inhibitor that causes histone hyperacetylation in living cells. In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC-2 in a concentration-dependent fashion but had no effect on the activity of the prototypical histone acetyltransferase GCN5. Acetylated histone H3-specific Western blots were used to monitor histone acetylation in HCT-8 colon carcinoma cells treated with CI-994 in vitro. CI-994 induced hyperacetylation of H3 in a time- and dose-dependent fashion. H3 hyperacetylation was detectable as early as 30 min after the addition of CI-994 to cells. These data demonstrate that inhibition of HDAC is an early event in cells treated with CI-994 and suggest that this inhibition is mechanistically related to the antitumor activity of this compound.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-720
    Nombre del producto:
    Anti-HDAC1 Antibody

  • Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing. 22198837

    The histone chaperone Rtt106 binds histone H3 acetylated at lysine 56 (H3K56ac) and facilitates nucleosome assembly during several molecular processes. Both the structural basis of this modification-specific recognition and how this recognition informs Rtt106 function are presently unclear. Guided by our crystal structure of Rtt106, we identified two regions on its double-pleckstrin homology domain architecture that mediated histone binding. When histone binding was compromised, Rtt106 localized properly to chromatin but failed to deliver H3K56ac, leading to replication and silencing defects. By mutating analogous regions in the structurally homologous chromatin-reorganizer Pob3, we revealed a conserved histone-binding function for a basic patch found on both proteins. In contrast, a loop connecting two β-strands was required for histone binding by Rtt106 but was dispensable for Pob3 function. Unlike Rtt106, Pob3 histone binding was modification-independent, implicating the loop of Rtt106 in H3K56ac-specific recognition in vivo. Our studies described the structural origins of Rtt106 function, identified a conserved histone-binding surface, and defined a critical role for Rtt106:H3K56ac-binding specificity in silencing and replication-coupled nucleosome turnover.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-677

  • An essential role for a mammalian SWI/SNF chromatin-remodeling complex during male meiosis. 22318225

    Germ cell development and gametogenesis require genome-wide transitions in epigenetic modifications and chromatin structure. These changes include covalent modifications to the DNA and histones as well as remodeling activities. Here, we explore the role of the mammalian SWI/SNF chromatin-remodeling complex during spermatogenesis using a conditional allele of the ATPase subunit, brahma-related gene 1 (Brg1, or Smarca4). Not only do BRG1 levels peak during the early stages of meiosis, genetic ablation of Brg1 in murine embryonic gonocytes results in arrest during prophase of meiosis I. Coincident with the timing of meiotic arrest, mutant spermatocytes accumulate unrepaired DNA and fail to complete synapsis. Furthermore, mutant spermatocytes show global alterations to histone modifications and chromatin structure indicative of a more heterochromatic genome. Together, these data demonstrate a requirement for BRG1 activity in spermatogenesis, and suggest a role for the mammalian SWI/SNF complex in programmed recombination and repair events that take place during meiosis.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Genome-wide profiling of histone H3 lysine 9 acetylation and dimethylation in Arabidopsis reveals correlation between multiple histone marks and gene expression. 20054610

    Lysine residue 9 of histone H3 can either be acetylated or mono-, di-, or tri-methylated. These epigenetic states have a diverse impact on regulating gene transcriptional activity and chromatin organization. H3K9ac is invariably correlated with transcriptional activation, whereas H3K9me2 has been reported to be mainly located in constitutive heterochromatin in Arabidopsis. Here, we present epigenetic landscapes for histone H3 lysine 9 acetylation (H3K9ac) and dimethylation (H3K9me2) in Arabidopsis seedlings. The results show that H3K9ac targeted 5,206 non-transposable element (non-TE) genes and 321 transposable elements (TEs), whereas H3K9me2 targeted 2,281 TEs and 1,112 non-TE genes. H3K9ac was biased towards the 5' end of genes and peaked at the ATG position, while H3K9me2 tended to span the entire gene body. H3K9ac correlated with high gene expression, while H3K9me2 correlated with low expression. Analyses of H3K9ac and H3K9me2 with the available datasets of H3K27me3 and DNA methylation revealed a correlation between the occurrence of multiple epigenetic modifications and gene expression. Genes with H3K9ac alone were actively transcribed, while genes that were also modified by either H3K27me3 or DNA methylation showed a lower expression level, suggesting that a combination of repressive marks weakened the positive regulatory effect of H3K9ac. Furthermore, we observed a significant increase of the H3K9ac modification level of selected target genes in hda19 (histone deacetylase 19) mutant seedlings, which indicated that HDA19 plays an important role in regulating the level of H3K9ac and thereby influencing the transcriptional activity in young seedlings.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-352
    Nombre del producto:
    Anti-acetyl-Histone H3 (Lys9) Antibody

  • Schizosaccharomyces pombe Hst4 functions in DNA damage response by regulating histone H3 K56 acetylation. 18344406

    The packaging of eukaryotic DNA into chromatin is likely to be crucial for the maintenance of genomic integrity. Histone acetylation and deacetylation, which alter chromatin accessibility, have been implicated in DNA damage tolerance. Here we show that Schizosaccharomyces pombe Hst4, a homolog of histone deacetylase Sir2, participates in S-phase-specific DNA damage tolerance. Hst4 was essential for the survival of cells exposed to the genotoxic agent methyl methanesulfonate (MMS) as well as for cells lacking components of the DNA damage checkpoint pathway. It was required for the deacetylation of histone H3 core domain residue lysine 56, since a strain with a point mutation of its catalytic domain was unable to deacetylate this residue in vivo. Hst4 regulated the acetylation of H3 K56 and was itself cell cycle regulated. We also show that MMS treatment resulted in increased acetylation of histone H3 lysine 56 in wild-type cells and hst4Delta mutants had constitutively elevated levels of histone H3 K56 acetylation. Interestingly, the level of expression of Hst4 decreased upon MMS treatment, suggesting that the cell regulates access to the site of DNA damage by changing the level of this protein. Furthermore, we find that the phenotypes of both K56Q and K56R mutants of histone H3 were similar to those of hst4Delta mutants, suggesting that proper regulation of histone acetylation is important for DNA integrity. We propose that Hst4 is a deacetylase involved in the restoration of chromatin structure following the S phase of cell cycle and DNA damage response.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-677

  • Epigenetic regulation of thy-1 by histone deacetylase inhibitor in rat lung fibroblasts. 20724553

    Thy-1 is a cell surface glycoprotein present on normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis. Thy-1 correlates inversely with fibrogenic phenotypic characteristics and functions as a "fibrosis suppressor." Promoter region hypermethylation can silence Thy-1 expression in fibroblastic foci, suggesting that epigenetic regulation is important in programming the fibrotic phenotype. We examined whether histone modifications are important in regulating Thy-1 expression in lung fibroblasts. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) restored Thy-1 expression in Thy-1(-) cells in a time-dependent and concentration-dependent fashion and was associated with enrichment of histone acetylation. Chromatin immunoprecipitation demonstrated Thy-1 depletion of trimethylated H3K27 after 24 hours of TSA treatment, concurrent with enrichment of trimethylated H3K4 and acetylated H4. Bisulfite sequencing of the Thy-1 promoter region revealed demethylation of the previously hypermethylated CpG sites after treatment with TSA. Although Thy-1 was hypermethylated in Thy-1(-) lung fibroblasts, we observed that Thy-1(-) cells have lower global DNA methylation compared with Thy-1(+) lung fibroblasts, which was partially reversed by TSA treatment. TSA treatment up-regulates total methyltransferase activity in these cells. Our data indicate that Thy-1 silencing is regulated by histone modifications in addition to promoter hypermethylation in lung fibroblasts. Additionally, our findings indicate that alteration of histone modifications alters DNA methylation. Understanding the molecular hierarchy of events with respect to reactivation of transcription and reversal of histone modification will be critical to understand and modify the regulated expression of Thy-1, a tumor-supressor and fibrosis-suppressor gene.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Analysis of the Relationships between DNA Double-Strand Breaks, Synaptonemal Complex and Crossovers Using the Atfas1-4 Mutant. 26147458

    Chromatin Assembly Factor 1 (CAF-1) is a histone chaperone that assembles acetylated histones H3/H4 onto newly synthesized DNA, allowing the de novo assembly of nucleosomes during replication. CAF-1 is an evolutionary conserved heterotrimeric protein complex. In Arabidopsis, the three CAF-1 subunits are encoded by FAS1, FAS2 and MSI1. Atfas1-4 mutants have reduced fertility due to a decrease in the number of cells that enter meiosis. Interestingly, the number of DNA double-strand breaks (DSBs), measured by scoring the presence of γH2AX, AtRAD51 and AtDMC1 foci, is higher than in wild-type (WT) plants, and meiotic recombination genes such AtCOM1/SAE2, AtBRCA1, AtRAD51 and AtDMC1 are overexpressed. An increase in DSBs in this mutant does not have a significant effect in the mean chiasma frequency at metaphase I, nor a different number of AtMLH1 nor AtMUS81 foci per cell compared to WT at pachytene. Nevertheless, this mutant does show a higher gene conversion (GC) frequency. To examine how an increase in DSBs influences meiotic recombination and synaptonemal complex (SC) formation, we analyzed double mutants defective for AtFAS1 and different homologous recombination (HR) proteins. Most showed significant increases in both the mean number of synapsis initiation points (SIPs) and the total length of AtZYP1 stretches in comparison with the corresponding single mutants. These experiments also provide new insight into the relationships between the recombinases in Arabidopsis, suggesting a prominent role for AtDMC1 versus AtRAD51 in establishing interhomolog interactions. In Arabidopsis an increase in the number of DSBs does not translate to an increase in the number of crossovers (COs) but instead in a higher GC frequency. We discuss different mechanisms to explain these results including the possible existence of CO homeostasis in plants.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-164
    Nombre del producto:
    Anti-phospho-H2A.X (Ser139) Antibody