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PubMed1994

[The effect of silymarin, a hepatoprotective substance, on liver histones in irradiated rats].

Changes of concentration, total content of histones and relative portions of histone fractions were investigated in the liver of rats after administration of the hepatoprotective substance silymarin (70 mg/kg) and after gamma-irradiation of the whole body at a dose of 3 Gy, which were examined in 30 hours and in 7 days. Administration of silymarin alone considerably increased the concentration, particularly total content of extractable histones in the liver of rats examined in hour 30. They decreased below the level of control values after 7 days. The whole body irradiation at a dose 3 Gy of gamma-radiation caused a steep fall of the concentration and total content of histones in hour 30, which persisted also on day 7. Silymarin administered 1 hour before irradiation prevented quantitative changes of histones in hour 30, after irradiation the fall was still steeper than after irradiation without silymarin administration. As Tab. I shows, a significant decrease in the relative portion of histone fractions H2A+H2B was found in the extracted histone of the experimental animals of all 3 groups in hour 30, as well as a decrease in the fraction H1 after irradiation without silymarin administration. A decrease in the lysin-rich-histone portion was related to an increase in the relative portion of histone H3. In the rats which were administered silymarin 1 hour before irradiation these changes were found to persist until day 7, and they were related to an increase in the subfraction H1(0) within the histone fraction H1 (Tab II). Hence the results document that silymarin administration 1 hour before irradiation had a positive effect which was observed in all the investigated parameters in hour 30 after irradiation. But the radioprotective effect of silymarin was only temporary while until day 7 after irradiation histone variations were identical or still larger than after irradiation without silymarin administration.

Animals↗
PubMed1977

[Mechanism of histone action on mitochondrial energetics. Proton and cation transport across membrane].

The effect of lysine-rich histone on mitochondria was studied with respect to the cation transport and proton uptake across the membrane. Histone does not affect Ca2+ uptake or level in mitochondria. It extrudes Mg2+ by 30% with the utilization of substrates; in the presence of rotenone extrusion drops to about 18%. Dinitrophenol and ADP prevent the effect of histone. Mg2+ uptake is inhibited by 12% by histone. K+ extrusion by histone (by 50%) which depends on the oxidation of substrates, is enhanced by phosphate, and Mg2+ decreases (by 50%) the K+ extrusion. Histone prevents to some extent extrusion of K+ by Ca2+. Histone does not affect Na+ level in mitochondria, it blocks (by 50%) Na+ uptake in the presence of gramicidin, probably by forming a gramicidin-histone complex. Histone blocks proton uptake by mitochondria incubated in the presence of valinomycin or DNP. In the presence of DNP valinomycin-induced H+ uptake is not affected by histone. H+ uptake induced by nigericin is not affected by histone as well.

Animals↗
PubMedDate not supplied

[Increase in thyroxine level in blood plasma of hypothyroid rats after administering histones].

It has been shown that the administration of total histones (H1, H3, H2B, H2A, H4), the total histones without histones H4 (H1, H3, H2B, H2A), H1 histones at concentrations of 0.001 and 1 microgram per 100 g of body weight (low and high concentrations) to intact rats during 6 days leads to the decrease of T4 amount in the blood plasm. The total histones and histone H1 at low concentration decrease the T4 amount by the coefficients 5.2 and 5.8 respectively. The corresponding coefficients for high concentration are 2.6 and 1.2. There is no difference in the action of the total histones and H1 histone at low concentration. Low concentration of histones is more effective for the decrease of T4 amount than the high one or than the antithyroid agents mercasolyl and LiCl (3 mg and 2 mM per .100 g of body weight), which decrease the amount of T4 in intact rats by the coefficient 3.6 in 38 days. Administration of histones decreases the amount of T4 in the intact rats but, on the contrary, the 3-4 fold increase is observed in hypothyroid rats, so the amount of T4 is practically reverted to the level of intact rats. The mechanism of regulation of the amount of T4 by histones is discussed.

Animals↗
PubMed1997

The effect of histone-mRNA interaction in protein synthesis.

The effect of lysine-rich and arginine-rich histones on selective inhibition of translation of mRNAs of tobacco mosaic virus (TMV), brome mosaic virus (BMV) and luciferase, in rabbit reticulocyte (RRL) was evaluated. Nuclease-treated RRL were supplemented with an appropriate mRNA and incubated with lysine-rich or arginine-rich histones at 5 and 2.5 micrograms/100 microliters lysate at 30 degrees C. Protein synthesis was measured as incorporation of 3H-leucine into protein for 24 min. The lysine-rich histone was more inhibitory than arginine-rich histone. At 5 and 2.5 micrograms/100 microliters lysate concentration, the lysine-rich histone inhibited translation of TMV mRNA by 57% and 35%, respectively, after 24 min. The corresponding values for arginine-rich histone were 31% and 13%. Both histones had a more inhibitory effect on the translation of viral mRNA than luciferase mRNA. Arginine-rich histone at 2.5 micrograms/100 microliters lysate did not cause any inhibition of luciferase mRNA. The spectrophotometric analysis of histone-mRNA mixtures at 280 nm indicated that, compared with arginine-rich histone, lysine-rich histone had a stronger affinity for mRNA.

Animals↗
PubMed2004

In vitro targeting reveals intrinsic histone tail specificity of the Sin3/histone deacetylase and N-CoR/SMRT corepressor complexes.

The histone code is among others established via differential acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). To unambiguously determine the histone tail specificity of HDAC-containing complexes, we have established an in vitro system consisting of nucleosomal templates reconstituted with hyperacetylated histones or recombinant histones followed by acetylation with native SAGA or NuA4. Selective targeting of the mammalian Sin3/HDAC and N-CoR/SMRT corepressor complexes by using specific chimeric repressors created a near physiological setting to assess their histone tail specificity. Recruitment of the Sin3/HDAC complex to nucleosomal templates preacetylated with SAGA or NuA4 resulted in deacetylation of histones H3 and H4, whereas recruitment of N-CoR/SMRT resulted in deacetylation of histone H3 only. These results provide solid evidence that HDAC-containing complexes display distinct, intrinsic histone tail specificities and hence may function differently to regulate chromatin structure and transcription.

Animals↗
PubMed2005

Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair.

Many recent studies have demonstrated recruitment of chromatin-modifying enzymes to double-strand breaks. Instead, we wanted to examine chromatin modifications during the repair of these double-strand breaks. We show that homologous recombination triggers the acetylation of N-terminal lysines on histones H3 and H4 flanking a double-strand break, followed by deacetylation of H3 and H4. Consistent with a requirement for acetylation and deacetylation during homologous recombination, Saccharomyces cerevisiae with substitutions of the acetylatable lysines of histone H4, deleted for the N-terminal tail of histone H3 or H4, deleted for the histone acetyltransferase GCN5 gene or the histone deacetylase RPD3 gene, shows inviability following induction of an HO lesion that is repaired primarily by homologous recombination. Furthermore, the histone acetyltransferases Gcn5 and Esa1 and the histone deacetylases Rpd3, Sir2, and Hst1 are recruited to the HO lesion during homologous recombinational repair. We have also observed a distinct pattern of histone deacetylation at the donor locus during homologous recombination. Our results demonstrate that dynamic changes in histone acetylation accompany homologous recombination and that the ability to modulate histone acetylation is essential for viability following homologous recombination.

Acetylation↗
PubMed2002

Kinetic analysis of histone acetylation turnover and Trichostatin A induced hyper- and hypoacetylation in alfalfa.

Dynamic histone acetylation is a characteristic of chromatin transcription. The first estimates for the rate of acetylation turnover of plants are reported, measured in alfalfa cells by pulse, pulse-chase, and steady-state acetylation labeling. Acetylation turnover half-lives of about 0.5 h were observed by all methods used for histones H3, H4, and H2B. This is consistent with the rate at which changes in gene expression occur in plants. Treatment with histone deacetylase inhibitor Trichostatin A (TSA) induced hyperacetylation at a similar rate. Replacement histone variant H3.2, preferentially localized in highly acetylated chromatin, displayed faster acetyl turnover. Histone H2A with a low level of acetylation was not subject to rapid turnover or hyperacetylation. Patterns of acetate labeling revealed fundamental differences between histone H3 versus histones H4 and H2B. In H3, acetylation of all molecules, limited by lysine methylation, had similar rates, independent of the level of lysine acetylation. Acetylation of histones H4 and H2B was seen in only a fraction of all molecules and involved multiacetylation. Acetylation turnover rates increased from mono- to penta- and hexaacetylated forms, respectively. TSA was an effective inhibitor of alfalfa histone deacetylases in vivo and caused a doubling in steady-state acetylation levels by 4-6 h after addition. However, hyperacetylation was transient due to loss of TSA inhibition. TSA-induced overexpression of cellular deacetylase activity produced hypoacetylation by 18 h treatment with enhanced acetate turnover labeling of alfalfa histones. Thus, application of TSA to change gene expression in vivo in plants may have unexpected consequences.

Acetates↗
PubMed2002

Induction of histone acetylation and inhibition of growth of mouse erythroleukemia cells by S-allylmercaptocysteine.

Growth-inhibitory effects on DS19 mouse erythroleukemia cells were seen in the micromolar concentration range with allicin and S-allylmercaptocysteine and in the millimolar range with allyl butyrate, allyl phenyl sulfone, and S-allyl cysteine. Increased acetylation of histones was induced by incubation of cells with the allyl compounds at concentrations similar to those that resulted in the inhibition of cell proliferation. The induction of histone acetylation by S-allylmercaptocysteine was also observed in Caco-2 human colon cancer cells and T47D human breast cancer cells. In contrast to the effect on histone acetylation, there was a decrease in the incorporation of phosphate into histones when DS19 cells were incubated with 25 microM S-allylmercaptocysteine. Histone deacetylase activity was inhibited by allyl butyrate, but there was little or no effect with the allyl sulfur compounds examined in this study. A similar degree of downregulation of histone deacetylase and histone acetyltransferase was observed when DS19 cells were incubated with S-allylmercaptocysteine or allyl isothiocyanate. The induction of histone acetylation by S-allylmercaptocysteine was not blocked by a proteasome inhibitor. The mechanism by which S-allylmercaptocysteine induces histone acetylation remains to be characterized. It may be related in part to metabolism to allyl mercaptan, which is a more effective inhibitor of histone deacetylase.

Acetylation↗
PubMed1996

The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation.

Posttranslational modifications of histones in chromatin are emerging as an important mechanism in the regulation of gene expression. Changes in histone acetylation levels occur during many nuclear processes such as replication, transcriptional silencing, and activation. Histone acetylation levels represent the result of a dynamic equilibrium between competing histone deacetylase(s) and histone acetylase(s). We have used two new specific inhibitors of histone deacetylase, trichostatin A (TSA) and trapoxin (TPX), to probe the effect of histone hyperacetylation on gene expression. We confirm that both drugs block histone deacetylase activity and have no detectable effects on histone acetylation rates in human lymphoid cell lines. Treatment with either TSA or TPX results in the transcriptional activation of HIV-1 gene expression in latently infected cell lines. In contrast, TSA and TPX cause a rapid decrease in c-myc gene expression and no change in the expression of the gene for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using differential display to compare the differences in gene expression between untreated cells and cells treated with TSA, we found that the expression of approximately 2% of cellular genes (8 genes out of approximately 340 examined) changes in response to TSA treatment. These results demonstrate that the transcriptional regulation of a restricted set of cellular genes is uniquely sensitive to the degree of histone acetylation in chromatin.

Acetylation↗
PubMed2004

Histone modification enzymes: novel targets for cancer drugs.

In eukaryotes, genomic DNA is packaged with histone proteins into the cell nucleus as chromatin, condensing the DNA > 10,000-fold. Chromatin is highly dynamic and exerts profound control on gene expression. Localised chromatin decondensation facilitates access of nuclear machinery. Chromatin displays epigenetic inheritance, in that changes in its structure can pass to the next generation independently of the DNA sequence itself. It is now clear that the post-translational modification of histones, for example, acetylation, methylation and phosphorylation, plays a crucial role in the regulation of nuclear function through the 'histone code'. There has been significant progress in identifying and understanding the enzymes that control these complex processes, in particular histone acetyltransferases and histone deacetylases. The exciting discovery that compounds inhibiting histone deacetylase activity also have antitumour properties has focused attention on their use as anticancer drugs. As a consequence, there is ongoing evaluation of several histone deacetylase inhibitor compounds in Phase I and II clinical trials with promising early results. It is likely that many of the enzymes involved in the control of histone modification will provide therapeutic opportunities for the treatment of cancer, including histone methyltransferases and Aurora kinases.

Acetylation↗
PubMed1986

The assay of the activity of protein kinase C with the synthetic oligopeptide substrate designed for histone kinase II.

The activity of histone kinase II was determined on the basis of its ability to phosphorylate the nonapeptide Ala-Ala-Ala-Ser-Phe-Lys-Ala-Lys-Lys-amide designed previously as a specific substrate for this enzyme. Histone kinase II was purified from calf thymus extract by DEAE-cellulose chromatography followed by hydroxylapatite chromatography and high-performance liquid chromatography on a Protein Analysis column (I-125). The Mr value of histone kinase II estimated by the latter method was 50,000-55,000, but several observations indicated that histone kinase II was a product of a proteolytic process. Since the substrate specificity determinants for histone kinase II known from our previous investigations are very similar to those for protein kinase C, it was presumable that histone kinase II was the proteolytic fragment of protein kinase C. Therefore, the nonapeptide was tested as a substrate for protein kinase C prepared from rabbit brain extract by DEAE-cellulose chromatography. The activity of histone kinase II was also detected in brain extract. Histone kinase II was eluted from the DEAE-cellulose in the known position of the proteolytic fragment of protein kinase C. The nonapeptide Ala-Ala-Ala-Ser-Phe-Lys-Ala-Lys-Lys-amide proved to be a better substrate than H1 histone for the detection of the activity of protein kinase C because it was not phosphorylated by the cAMP-dependent protein kinase and the Vmax of protein kinase C was about one order of magnitude higher with the peptide than with H1 histone. The apparent Km of protein kinase C for the peptide was identical with that of histone kinase II (0.2 mM).

Animals↗
PubMed1992

Differential Expression of Histone H3 Gene Variants during Cell Cycle and Somatic Embryogenesis in Alfalfa.

Northern analysis has revealed substantial differences in mRNA accumulation of the two histone H3 gene variants represented by pH3c-1 and pH3c-11 cDNA clones. Both in partially synchronized cell suspension cultures and in protoplast-derived cells from alfalfa, Medicago varia, the maximal level of the histone H3-1 gene transcript coincided with the peak in [(3)H]thymidine incorporation. Histone H3-11 mRNA was detectable in cells throughout the period of the cell cycle studied. Various stress factors such as medium replacement, enzyme digestion of the cell wall, osmotic shock, and auxin treatment considerably increased the level of the histone H3-11 transcript. In alfalfa (Medicago sativa), the presence of H3-11 mRNA in unorganized tissues of microcallus suspension and in somatic embryos induced by auxin treatment supports the idea that this H3 variant exists in a continously active state of transcription. During embryo development, the early globular stage embryos showed increased accumulation of histone H3-11 mRNA in comparison with the later stages. The highest level of the histone H3-1 transcript was detectable 1 day after treatment of callus tissues with 2,4-dichlorophenoxyacetic acid. Somatic embryos contained appreciable levels of histone H3-1 transcripts at all stages of somatic embryo development. These observations suggest that the histone H3-1 gene belòngs to the class of replication-dependent histone genes. The histone H3-11 gene showed characteristics of a constitutively expressed replacement-type histone gene, with a specific characteristic that external factors can influence the level of gene transcription.

Journal Article↗
PubMed1983

Conformations and flexibilities of histones and high mobility group (HMG) proteins in chromatin structure and function.

The packaging of the enormous lengths of eukaryotic DNA into the different conformational states of chromosomes is controlled very largely by an equal total mass of the histones, H1, H2A, H2B, H3 and H4. Histone sequences, sequence conservations, postsynthetic chemical modifications and studies of histone conformations and interactions show clearly that histones are multi-domain proteins. The N-terminal domains of all histones and the C-terminal domains of H1, H2A and H2B are flexible random coils, while the C-terminal regions of H3 and H4 and the central regions of H1, H2A and H2B are structured. Histones H3 and H4 are essential for nucleosome structure and interact with DNA to give the nucleus of the nucleosome structure, which is completed by interactions of the conserved structured regions of (H2A, H2B) dimers and H1. The flexible domains of all the histones are very basic and contain all the sites of reversible chemical modifications: acetylation of lysines in the core histones and phosphorylation of serines and threonines in histone H1. Strict correlations have been observed (i) between acetylation and DNA processing and (ii) between H1 phosphorylation and chromosome condensation. In addition to histone acetylation, active chromatin is also associated with high mobility group (HMG) proteins 14 and 17. These proteins are completely flexible under all solution conditions and their native structures must be imposed by their binding sites in active chromatin. The function of flexibility in these chromosomal proteins is not understood but is probably related to the enormous lengths of DNA which have to be controlled in the structures and function of chromosomes.

Chromatin↗
PubMed2005

New method to detect histone acetylation levels by flow cytometry.

BACKGROUND: Reversible histone acetylation affects chromatin structural organization, thus regulating gene expression and other nuclear events. Levels of histone acetylation are tightly modulated in normal cells, and alterations of their regulating mechanisms have been shown to be involved in tumorigenesis. METHODS: We developed a new flow cytometric technique for detection of histone acetylation, based on a specific monoclonal antibody that recognizes acetylated histone tails. Bivariate analysis for histone acetylation levels and DNA were performed to study modulation of chromatin organization during the cell cycle and after induction of histone hyperacetylation by the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). Histone acetylation and transcription levels were monitored during differentiation induced by retinoic acid alone or in combination with TSA. Blood samples from patients were analyzed with the described protocol to monitor the effects of HDAC inhibitors in vivo and validate the developed protocol for clinical usage. RESULTS: Flow cytometric detection of acetylation status can successfully detect modifications induced by HDAC inhibitor treatment in vivo as demonstrated by analysis of various blood samples from patients treated with valproic acid. Changes in acetylation levels during the cell cycle demonstrated a reproducible increase in histone acetylation during the replication phase that was subsequently decreased at the G2M entrance, thus paralleling the behavior of DNA replication and transcriptional activity. CONCLUSIONS: Multiparameter analysis of histone acetylation and expression of molecular markers, DNA ploidy, and/or cell cycle kinetics can provide a quick and statistically reliable tool for the diagnosis and evaluation of treatment efficacy in clinical trials using HDAC inhibitors.

Acetylation↗
PubMed1980

Regulation of specific genes during the cell cycle. Utilization of homologous cDNAs and cloned sequences for studying histone gene expression in human cells.

Evidence for differential gene expression during the cell cycle and approaches for studying cell-cycle-stage specific gene expression are summarized. Attention is focused on regulation of histone gene expression during the cell cycle of continuously dividing cells and after stimulation of nondividing cells to proliferate. The level(s) at which control of histone gene expression occurs and the possible involvement of chromosomal proteins in the regulation of histone gene expression are discussed. The preparation of cloned human histone sequences and their use in studying the structural and functional properties of human histone genes are presented. Index Entries: Cell cycle, gene regulation during; gene regulation, during the cell cycle; regulation of specific genes, during the cell cycle; DNAs, homologous, and histone gene expression; cloned DNAs, and histone gene expression; histone gene expression; gene expression, histone; cloned human histone sequences.

Base Sequence↗
PubMed2026

Both L-Lactyl and D-Lactyl Enantiomers Modify Histones in Mouse Testis.

Dynamic histone posttranslational modifications are crucial to precisely orchestrate gene expression programs. The recently discovered histone lysine lactylation has already been explored in various pathological contexts, but less in normal tissues. This modification exists as two enantiomers, L- and D-lactylation; the former may more likely modify histones due to abundant L-lactate produced by glycolysis. Here, we report the identification by proteomics of L- and D-lactylation on lysines of histones H3 and H4 in mouse testis. We developed a targeted proteomic analysis of histone peptides using synthetic sequences modified by L- or D-lactyl, to acquire reliable identification and quantification data. Some histone peptides bearing either enantiomer are separated by reversed-phase chromatography. Interestingly, despite the fact that L-lactate is much more abundant than D-lactate in mouse testis, we estimated abundance ratios of L-over D-lactylation to lie between 0.4 and 1.6 on seven residues of histones H3 and H4. Next, targeted proteomic analyses were performed on histones extracted from meiotic and postmeiotic male germ cells (spermatocytes and round spermatids, respectively), which are known to use L-lactate as a main source of energy. Nonetheless, residues 18 and 23 of histone H3 (H3K18 and H3K23) were reliably quantified and shown to harbor balanced amounts of both enantiomers. The stoichiometry of lactylation is low over the whole sequence of H3 and H4, representing about 0.01 to 0.44%: this contrasts with acetylation which exists at up to 25 to 35% relative abundances on some N-terminal lysines. Yet, lactylation appears to be more abundant than acetylation on the C-terminal half of H3 and H4, where the latter modification is scarce. Collectively, our results suggest a mechanism producing a mixture of the two enantiomers of lactate, or of a more direct substrate for lactylation, that leads to the modification of histones by L- and D-lactylation.

Animals↗
PubMed2007

Selective recognition of acetylated histones by bromodomains in transcriptional co-activators.

Bromodomains are present in many chromatin-associated proteins such as the SWI/SNF and RSC chromatin remodelling and the SAGA HAT (histone acetyltransferase) complexes, and can bind to acetylated lysine residues in the N-terminal tails of the histones. Lysine acetylation is a histone modification that forms a stable epigenetic mark on chromatin for bromodomain-containing proteins to dock and in turn regulate gene expression. In order to better understand how bromodomains read the 'histone code' and interact with acetylated histones, we have tested the interactions of several bromodomains within transcriptional co-activators with differentially acetylated histone tail peptides and HAT-acetylated histones. Using GST (glutathione S-transferase) pull-down assays, we show specificity of binding of some bromodomains to differentially acetylated H3 and H4 peptides as well as HAT-acetylated histones. Our results reveal that the Swi2/Snf2 bromodomain interacts with various acetylated H3 and H4 peptides, whereas the Gcn5 bromodomain interacts only with acetylated H3 peptides and tetra-acetylated H4 peptides. Additionally we show that the Spt7 bromodomain interacts with acetylated H3 peptides weakly, but not with acetylated H4 peptides. Some bromodomains such as the Bdf1-2 do not interact with most of the acetylated peptides tested. Results of the peptide experiments are confirmed with tests of interactions between these bromodomains and HAT-acetylated histones. Furthermore, we demonstrate that the Swi2/Snf2 bromodomain is important for the binding and the remodelling activity of the SWI/SNF complex on hyperacetylated nucleosomes. The selective recognition of the bromodomains observed in the present study accounts for the broad effects of bromodomain-containing proteins observed on binding to histones.

Acetylation↗
PubMed1994

Properties of the yeast nuclear histone deacetylase.

A nuclear histone deacetylase from yeast was partially purified and some of its characteristics were studied. Histone deacetylase activity was stimulated in vitro by high-mobility-group nonhistone chromatin proteins 1 and 2 and ubiquitin and inhibited by spermine and spermidine, whereas n-butyrate had no significant inhibitory effect. Like the mammalian enzyme, partially purified histone deacetylase from yeast was strongly inhibited by trichostatin A. However, in crude extract preparations the yeast enzyme was not inhibited and treatment with trichostatin in vivo did not show any effect, either on the histone acetylation level or on cell viability. At low ionic strength, the enzyme can be isolated as a complex of high molecular mass that is much less inhibited by trichostatin A than is partially purified histone deacetylase activity. Furthermore, radiolabelled oligonucleosomes were more efficiently deacetylated by the complex than by the low-molecular-mass form of the enzyme. The histone deacetylase activity was separated from a polyamine deacetylase activity and its specificity studied. Using h.p.l.c.-purified core histone species as substrate, histone deacetylase from yeast is able to deacetylate all core histones with a slight preference for H3. Our results support the idea that the yeast histone deacetylase may act as a high-molecular-mass complex in vivo.

Cell Nucleus↗