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At least 19 recordsLinked to original sources
PubMed2003

The sounds of silence--histone deacetylation meets histone methylation.

The repression of gene activity and the maintenance of the repressed state are fundamental requirements of cell differentiation, ordered embryonic development and tissue integrity. Furthermore, large regions of the genome such as centromeres and telomeres have a structural function and have to be kept transcriptionally inactive to be functional. In both cases the transcriptional silencing is accomplished through a dense packaging of the corresponding DNA into heterochromatin or heterochromatin-like structures. In this minireview we summarise recent findings, which point towards a major function of posttranslational histone modifications in the process of establishment and maintenance of condensed heterochromatin. The physical association of two enzymatic activities, histone methylation and histone deacetylation, which are thought to be involved in transcriptional silencing, provide the framework of a molecular model of how heterochromatin is initiated and maintained during cell division and differentiation.

DNA Methylation↗
PubMed2004

Transcript profiling in Arabidopsis reveals complex responses to global inhibition of DNA methylation and histone deacetylation.

Blocking histone deacetylation with trichostatin A (TSA) or blocking cytosine methylation using 5-aza-2'-deoxycytosine (aza-dC) can derepress silenced genes in multicellular eukaryotes, including animals and plants. We questioned whether DNA methylation and histone deacetylation overlap in the regulation of endogenous plant genes by monitoring changes in expression of approximately 7800 Arabidopsis thaliana genes following treatment with azadC, TSA, or both chemicals together. RNA levels for approximately 4% of the genes were reproducibly changed 3-fold or more by at least one treatment. Distinct subsets of genes are up-regulated or down-regulated in response to aza-dC, TSA, or simultaneous treatment with both chemicals, with little overlap among subsets. Surprisingly, the microarray data indicate that TSA and aza-dC are often antagonistic rather than synergistic in their effects. Analysis of green fluorescent protein transgenic plants confirmed this finding, showing that TSA can block the up-regulation of silenced green fluorescent protein transgenes in response to aza-dC or a ddm1 (decrease in DNA methylation 1) mutation. Our results indicate that global inhibition of DNA methylation or histone deacetylation has complex, nonredundant effects for the majority of responsive genes and suggest that activation of some genes requires one or more TSA-sensitive deacetylation events in addition to cytosine demethylation.

Acetylation↗
PubMed2006

Epigenetics of gene expression in human hepatoma cells: expression profiling the response to inhibition of DNA methylation and histone deacetylation.

BACKGROUND: DNA methylation and histone deacetylation are epigenetic mechanisms that play major roles in eukaryotic gene regulation. We hypothesize that many genes in the human hepatoma cell line HepG2 are regulated by DNA methylation and histone deacetylation. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) to inhibit DNA methylation with and/or Trichostatin A (TSA) to inhibit histone deacetylation should allow us to identify genes that are regulated epigenetically in hepatoma cells. RESULTS: 5-aza-dC had a much larger effect on gene expression in HepG2 cells than did TSA, as measured using Affymetrix HG-U133 Plus 2.0 microarrays. The expression of 1504 probe sets was affected by 5-aza-dC (at p < 0.01), 535 probe sets by TSA, and 1929 probe sets by the combination of 5-aza-dC and TSA. 5-aza-dC treatment turned on the expression of 211 probe sets that were not detectably expressed in its absence. Expression of imprinted genes regulated by DNA methylation, such as H19 and NNAT, was turned on or greatly increased in response to 5-aza-dC. Genes involved in liver processes such as xenobiotic metabolism (CYP3A4, CYP3A5, and CYP3A7) and steroid biosynthesis (CYP17A1 and CYP19A1), and genes encoding CCAAT element-binding proteins (C/EBPalpha, C/EBPbeta, and C/EBPgamma) were affected by 5-aza-dC or the combination. Many of the genes that fall within these groups are also expressed in the developing fetal liver and adult liver. Quantitative real-time RT-PCR assays confirmed selected gene expression changes seen in microarray analyses. CONCLUSION: Epigenetics play a role in regulating the expression of several genes involved in essential liver processes such as xenobiotic metabolism and steroid biosynthesis in HepG2 cells. Many genes whose expression is normally silenced in these hepatoma cells were re-expressed by 5-aza-dC treatment. DNA methylation may be a factor in restricting the expression of fetal genes during liver development and in shutting down expression in hepatoma cells.

Acetylation↗
PubMed2000

Molecular mechanism for silencing virally transduced genes involves histone deacetylation and chromatin condensation.

Virally transduced genes are often silenced after integration into the host genome. Chromatin immunoprecipitation and nuclease sensitivity experiments now demonstrate that silencing of the transgene is characterized by deacetylation of histone H4 lysines and chromatin condensation. Trichostatin A treatment results in dramatic reactivation of gene expression that is preceded by histone acetylation and chromatin decondensation. Analysis of individual histone H4 lysines demonstrate that chromatin domain opening is coincident with rapid acetylation of histone H4 K5, K12, and K16 and that maintenance of the open domain is correlated with acetylation of histone H4 K8. Removal of trichostatin A results in rapid deacetylation of histone H4 K8, chromatin condensation, and transcription silencing. The results suggest that deacetylation of histone H4 lysines and coincident chromatin condensation are critically involved in the silencing of virally transduced genes.

Acetylation↗
PubMed2005

Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation.

Assembly of silent chromatin domains in budding yeast involves the deacetylation of histone tails by Sir2 and the association of the Sir3 and Sir4 proteins with hypoacetylated histone tails. Sir2 couples deacetylation to NAD hydrolysis and the synthesis of a metabolite, O-acetyl-ADP-ribose (AAR), but the functional significance of NAD hydrolysis or AAR, if any, is unknown. Here we examine the association of the Sir2, Sir3, and Sir4 proteins with each other and histone tails. Our analysis reveals that deacetylation of histone H4-lysine 16 (K16), which is critical for silencing in vivo, is also critical for the binding of Sir3 and Sir4 to histone H4 peptides in vitro. Moreover, AAR itself promotes the association of multiple copies of Sir3 with Sir2/Sir4 and induces a dramatic structural rearrangement in the SIR complex. These results suggest that Sir2 activity modulates the assembly of the SIR complex through both histone deacetylation and AAR synthesis.

Binding Sites↗
PubMed2006

Activities of maturation-promoting factor (MPF) and mitogen-activated protein kinase (MAPK) are not required for the global histone deacetylation observed after germinal vesicle breakdown (GVBD) in porcine oocytes.

The acetylation of nuclear core histone has been suggested to work as an epigenetic mark for transmitting gene expression patterns to daughter cells. Global histone deacetylations, presumably involved in the reprogramming of the gene expression, have been observed after germinal vesicle breakdown (GVBD) in a cell cycle-dependent manner during meiotic maturation of mouse and porcine oocytes, although the regulation mechanism of histone deacetylation has not been studied well. In the present study, we examined the involvement of a crucial cell-cycle-regulator, maturation-promoting factor (MPF), and a meiosis-related kinase, mitogen-activated protein kinase (MAPK), in the global histone deacetylation during porcine oocyte maturation. In order to know whether the activities of MPF and MAPK were required, or the breakdown of GV membrane was sufficient, for the global histone deacetylation observed after GVBD, we artificially destroyed the GV membrane of the porcine immature oocytes. The artificial GV destruction (AGVD) induced histone deacetylation without the activation of MPF and MAPK. This deacetylation after AGVD was not affected by an MPF inhibitor, roscovitine, or an inhibitor of protein synthesis, cycloheximide, but was completely prevented by an inhibitor of histone deactylases (HDACs), trichostatine A. HDAC1 was present in the GV of the immature oocytes and localized on chromosomes after GVBD and AGVD. These results suggest that the MPF and MAPK activities were dispensable and the breakdown of the GV membrane was sufficient for the global histone deacetylation, which was catalyzed by HDAC activity.

Acetylation↗
PubMed2006

Histone deacetylation is required for orderly meiosis.

Histone acetylation is associated with a diversity of chromatin-related processes in mitosis. However, its roles in mammalian oocyte meiosis are largely unknown. In the present study, we first investigated in detail the acetylation changes during porcine oocyte maturation using a panel of antibodies specific for the critical acetylated forms of histone H3 and H4, and showed meiosis stage-dependent and lysine residue-specific patterns of histone acetylation. By using trichostatin A (TSA), a general inhibitor of histone deacetylases (HDACs), we further determined that selective inhibition of histone deacetylation (thereby maintaining hyperacetylation) delayed the onset of germinal vesicle breakdown and produced a high frequency of lagging chromosomes or chromatin bridges at anaphase and telophase I (AT-I), suggesting that histone deacetylation is required for orderly meiotic resumption and accurate chromosome segregation in porcine oocytes. In addition, we examined the localization and expression of HDAC1 by performing immunofluorescence and immunoblotting analysis. The results showed that subcellular translocation, expression level and phosphorylated modification of HDAC1 were temporally regulated and likely to coparticipate in the establishment of histone acetylation profiles in oocyte meiosis.

Acetylation↗
PubMed2005

Gene expression analysis reveals that histone deacetylation sites may serve as partitions of chromatin gene expression domains.

BACKGROUND: It has been a long-term puzzle whether chromatin can be further divided into distinct gene expression domains. Because histone deacetylation affects chromatin structure, that in turn may affect the expression of nearby genes, histone deacetylation sites may act to partition chromatin into different gene expression domains. In this article, we explore the relationship between histone deacetylation sites and gene expression patterns on the genome scale using different data sources, including microarray data measuring gene expression levels, microarray data measuring histone deacetylation sites, and information on regulatory targets of transcription factors. RESULTS: Using 269 Saccharomyces cerevisiae microarray datasets, histone deacetylation datasets, and regulatory targets of transcription factors assembled from the Yeast Proteome Database and ChIP-chip data, we found that histone deacetylation sites can reduce the level of co-expression of neighboring genes. CONCLUSION: Histone deacetylation sites may serve as possible partition sites for chromatin domains and affect gene expression.

Binding Sites↗
PubMed1989

A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation.

The inhibitory effects of 7-[N-(3-aminopropyl)amino]heptan-2-one (APAH) on N8-acetylspermidine deacetylation were studied. In in vitro studies, APAH produced inhibition (apparent Ki of 0.18 microM) of N8-acetylspermidine deacetylation by the 100,000g supernatant fraction of rat liver. This apparent Ki was 60-fold less than the apparent Km (11 microM) for deacetylation of the substrate, N8-acetylspermidine, suggesting that APAH could be a potent, effective inhibitor in vivo. APAH was administered to mice by intraperitoneal injection at a dose of 200 mg/kg, and polyamine and acetylpolyamine levels in liver and spleen were measured. In tissues of control mice, N8-acetylspermidine was not detectable but increased to detectable levels 30-360 min after APAH treatment. These data are consistent with inhibition of the deacetylase by APAH. Increases in putrescine and N1-acetylspermidine levels occurred in liver after APAH treatment with increases in N1-acetylspermidine levels observed in spleen. In HeLa cells, a significant increase in N8-acetylspermidine was observed following 24 h exposure to 10 microM APAH while no change occurred in the acetylation level of HeLa cell histones. In contrast, 24 h exposure to 10 mM sodium butyrate produced no change in N8-acetylspermidine levels and an increase in the acetylation level of histones H4 and H2B. These results suggest that APAH has a relatively selective inhibitory effect on N8-acetylspermidine but not histone deacetylation. This is the first report of significant levels of N8-acetylspermidine in animal tissues and of the effects of in vivo inhibition of N8-acetylspermidine deacetylase.

Acetylation↗
PubMed2002

Inhibition of histone deacetylation enhances endotoxin-stimulated transcription but does not reverse endotoxin tolerance.

Covalent modification of histones and the subsequent remodeling of chromatin have emerged as important mechanisms in regulating gene expression. In particular, recent identification of the enzyme families responsible for the steady-state balance of histone acetylation has served to redefine our understanding of these modifications as fundamental biochemical processes regulating transcription. Current evidence suggests that histone acetylation correlates positively with gene activation, while histone deacetylation acts to repress transcription. In this study, we examined the role of histone modification in the inflammatory response to endotoxin. We focused on the endotoxin-stimulated expression of the interleukin-1beta promoter and tested the hypotheses that persistent histone deacetylation was responsible for the decreased expression of this promoter observed after prolonged exposure to endotoxin, a manifestation of a phenomenon known as endotoxin tolerance. We found that histone deacetylase inhibitors enhanced endotoxin-stimulated transcription; however, deacetylation inhibitors could neither block the development of tolerance nor restore endotoxin sensitivity in a tolerant cell. Deacetylase inhibitors could not restore LPS-mediated transcription in tolerant cells. These results show that histone acetylation/deacetylation regulates, at least in part, the endotoxin-induced expression of inflammatory genes and that repressed transcription observed in endotoxin tolerance is not caused by enhanced activity of histone deacetylases.

Blotting, Northern↗
PubMed1983

Histone deacetylation is required for the maturation of newly replicated chromatin.

The effects of inhibiting histone deacetylation on the maturation of newly replicated chromatin have been examined. HeLa cells were labeled with [3H]thymidine in the presence or absence of sodium butyrate; control experiments demonstrated that butyrate did not significantly inhibit DNA replication for at least 70 min. Like normal nascent chromatin, chromatin labeled for brief periods (0.5-1 min) in the presence of butyrate was more sensitive to digestion with DNase I and micrococcal nuclease than control bulk chromatin. However, chromatin replicated in butyrate did not mature as in normal replication, but instead retained approximately 50% of its heightened sensitivity to DNase I. Incubation of mature chromatin in butyrate for 1 h did not induce DNase I sensitivity: therefore, the presence of sodium butyrate was required during replication to preserve the increased digestibility of nascent chromatin DNA. In contrast, sodium butyrate did not inhibit or retard the maturation of newly replicated chromatin when assayed by micrococcal nuclease digestion, as determined by the following criteria: 1) digestion to acid solubility, 2) rate of conversion to mononucleosomes, 3) repeat length, and 4) presence of non-nucleosomal DNA. Consistent with the properties of chromatin replicated in butyrate, micrococcal nuclease also did not preferentially attack the internucleosomal linkers of chromatin regions acetylated in vivo. The observation of a novel chromatin replication intermediate, which is highly sensitive to DNase I but possesses normal resistance to micrococcal nuclease, suggests that nucleosome assembly and histone deacetylation are not obligatorily coordinated. Thus, while deacetylation is required for chromatin maturation, histone acetylation apparently affects chromatin organization at a level distinct from that of core particle or linker, possibly by altering higher order structure.

Acetylation↗
PubMed1978

Sodium butyrate inhibits histone deacetylation in cultured cells.

Sodium butyrate in millimolar concentrations causes an accumulation of acetylated histone species in a variety of vertebrate cell lines. In all lines tested, butyrate caused hyperacetylation of H3 and H4, and in rat IRC8 cells, H2A and H2B were also affected. In Friend erythroleukemic cells, butyrate also induces the synthesis of a nonhistone chromosomal protein, IP25. butyrate does not affect the rate of histone acetylation in cell-free extracts of nuclei of Friend cells. Rather, this fatty acid inhibits histone deacetylation. Cell-free extracts of either control cells or butyrate-grown cells contain comparable levels of histone-deacetylating activity. This in vitro activity is inhibited by the addition of butyrate to the extracts. Thus butyrate appears to be an inhibitor of histone deacetylases both in vivo and in vitro.

Acetylation↗
PubMed2001

Regulation of CD21 expression by DNA methylation and histone deacetylation.

The complement receptor II (CD21) serves as a receptor for the complement component C3d of immune complexes on B lymphocytes. Expression of the CD21 gene is tightly regulated during B lymphocyte differentiation. Only mature B lymphocytes, but not pro-, pre- or plasma B lymphocytes, express CD21. There is evidence that cell type-specific expression is mediated by a silencer element located in the first intron. The CD21 promoter region contains a CpG island adjacent to the ATG start codon. We have analyzed the methylation status of this CpG island in B lymphoid cell lines representing the various differentiation stages of B lymphocyte development and primary lymphocytes. We found that the pro-, pre- and intermediate B lymphocytes contain a methylated CpG island and do not express CD21, whereas CD21-expressing mature B lymphocytes, plasma B lymphocytes and non-lymphoid cells carry a demethylated CD21 CpG island. To analyze whether the lack of CD21 expression in early B lymphocytes is due to inhibition by CpG methylation we have used 5-aza-2'-deoxycytidine to inhibit DNA methyltransferase activity. Treatment of pro-B lymphocytes with the drug resulted in expression of CD21. We have also applied Trichostatin A (TSA), an inhibitor of histone deacetylation, to determine whether the state of histone deacetylation affects the expression of CD21. We found that TSA induces expression of CD21 in early B lymphocytes. Thus CD21 expression is controlled by both methylation of the CD21 CpG island and chromatin modification through histone deacetylation in early B lymphocyte development.

Acetylation↗
PubMedDate not supplied

Histone deacetylation is directly involved in desilencing the expression of the catalytic subunit of telomerase in normal lung fibroblast.

The regulation of telomerase expression in normal cells is poorly understood. Moreover, the molecular mechanism underlying tumor-specific expression of telomerase remains unclear. We investigated the link between histone deacetylation and telomerase activity in normal lung and lung tumor cells. Four non-small-cell lung cancer (NSCLC) lines and one normal lung fibroblast line were tested for telomerase activity with or without Trichostatin A(TSA). The telomerase activity and the expression of telomerase associated components were determined by TRAP assay, RT-PCR analysis and Western blot analysis. All 4 NSCLC cell lines exposed to 1 microM TSA for 24 h had no change in telomerase activity or hTERT mRNA level. Telomerase activity was very low in normal lung fibroblasts (mrc-9) until exposed to 1 microM TSA for 24 h, at which time telomerase activity was readily detectable, with concomitant upregulation of hTERT mRNA (10-fold). The level of other telomerase associated components (hTER and TP1) were unaltered. Furthermore, 1 microM TSA exposure for 24 h did not alter the level of c-Myc or p21 mRNA. Immunodetection reveled that hTERT protein expression increased (approximately 6 fold) compared to c-Myc, p21, or gelsolin. The effect of TSA on hTERT expression is independent of DNA methylation as judged by 5-azacytidine (5aza) treatment. TSA effect on mrc-9 cells is unaltered even in the presence of 200 microg/ml cyclohexamide, suggesting a direct inhibition of histone deacetylation. Collectively, our study indicates that inhibition of histone deacetylation selectively regulates the transcriptional derepression of telomerase catalytic subunit in normal lung fibroblast cells compared to lung tumor cells.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Coupling of histone deacetylation to NAD breakdown by the yeast silencing protein Sir2: Evidence for acetyl transfer from substrate to an NAD breakdown product.

The Saccharomyces cerevisiae silencing protein Sir2 is the founding member of a universally conserved family of proteins that have been shown to possess NAD-dependent histone deacetylation and ADP-ribosylation activities. Here we show that histone deacetylation by Sir2 is coupled to cleavage of the high-energy bond that links the ADP-ribose moiety of NAD to nicotinamide. Analysis of the NAD cleavage products revealed the presence of nicotinamide, ADP-ribose, and a third product that appeared to be related to ADP-ribose. With the use of label transfer experiments, we show that the acetyl group in the histone substrate is transferred to this NAD breakdown product during deacetylation, forming a product that we conclude to be O-acetyl-ADP-ribose. Detection of this species strongly argues for obligate coupling of histone deacetylation to NAD breakdown by Sir2. We propose reaction mechanisms that could account for this coupling via acetyl-ADP-ribose formation. The unprecedented coupling of amide bond cleavage to cleavage of a high-energy bond raises the possibility that NAD breakdown by Sir2 plays an important role in silencing that is independent of its requirement for deacetylation.

Acetylation↗
PubMed2005

Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1beta in response to LPS.

It has been postulated that the progression of human pregnancy to term is, in part, the result of a relative maternal Th(2) immunological state. This can be activated in some cell types by modifying DNA methylation and histone acetylation status. We demonstrate that the molecular inhibition of histone deacetylation, using trichostatin A (TSA), in human choriodecidual explants leads to a massive increase in lipopolysaccharide (LPS)-stimulated IL-1beta. The inhibition of histone deacetylation had no effect on LPS-stimulated TNF-alpha production or production of the other cytokines studied (IL-10, IL-1 receptor antagonist). The molecular inhibition of DNA methylation and histone deacetylation, using 5-aza-2'-deoxycytidine and TSA, respectively, in human choriodecidual explants also results in an increase in the basal production of TNF-alpha but not that of IL-1beta. The differential response is unique, and the relative uncoupling of IL-1beta and TNF-alpha responsiveness may have importance in other biological systems and provide new therapeutic targets for pathologies where upregulation of IL-1beta is known to be a causative factor.

Acetylation↗
PubMed2001

Inhibition of histone deacetylation induces constitutive derepression of the beta interferon promoter and confers antiviral activity.

The induction of alpha/beta interferon (IFN-alpha/beta) genes constitutes one of the first responses of the cell to virus infection. The IFN-beta gene is constitutively repressed in uninfected cells and is transiently activated after virus infection. In this work we demonstrate that histone deacetylation regulates the silent state of the murine IFN-beta gene. Using chromatin immunoprecipitation (ChIP) assays, we show a direct in vivo correlation between the transcriptionally silent state and a state of hypoacetylation of histone H4 on the IFN-beta promoter region. Trichostatin A (TSA), a specific inhibitor of histone deacetylases, induced strong, constitutive derepression of the murine IFN-beta promoter stably integrated into a chromatin context, as well as the hyperacetylation of histone H4, without requiring de novo protein synthesis. We also show in this work that TSA treatment strongly enhances the endogenous IFN level and confers an antiviral state to murine fibroblastic L929 cells. Inhibition of histone deacetylation with TSA protected the cells against the lost of viability induced by vesicular stomatitis virus (VSV) and inhibited VSV multiplication. Using antibodies neutralizing IFN-alpha/beta, we show that the antiviral state induced by TSA is due to TSA-induced IFN production. The demonstration of the predominant role of histone deacetylation during the regulation of the constitutive repressed state of the IFN-beta promoter constitutes an interesting advance on the understanding of the negative regulation of this gene and opens up the possibility of new therapeutic perspectives.

Acetylation↗
PubMed1978

Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences.

Exposure of HeLa cells to Na butyrate leads to an accumulation of multiacetylated forms of histones H3 and H4. Our studies of histone acetylation in HeLa S-3 cells show that 7 mM butyrate suppresses the deacetylation of histones without influencing the rate of radioactive acetate incorporation. An alteration in nucleosome structure in highly acetylated chromatin is indicated by an increased rate of DNA degradation by DNase I. A close association of acetylated histones with the DNase I-sensitive sequences is confirmed by the finding that histones remaining after limited DNase I digestion are depleted in the multiacetylated forms of histones H3 and H4. DNase I treatment has also been found to selectively release [3H]acetyl-labeled H3 and H4 from avian erythrocyte nuclei under conditions previously shown to preferentially degrade the globlin genes in erthyrocyte chromatin. Our results are consistent with the view that histone acetylation provides a key to the mechanism for altering chromatin structure at the nucleosomal level, and that this may explain the selective DNase I sensitivity of transcriptionally active DNA sequences in different cell types.

Acetylation↗