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PubMed1991

Characterization and chromatin distribution of the H1 histones and high-mobility-group non-histone chromosomal proteins of trout liver and hepatocellular carcinoma.

The H1 histones serve as general repressors of gene expression by inducing the formation of a compact chromatin structure, whereas the high-mobility-group (HMG) non-histone chromosomal proteins have roles in maintaining the structure and function of transcriptionally active chromatin. The distribution of the H1 histone subtypes and HMG proteins among various trout tissues (liver, hepatocellular carcinoma, testis and erythrocyte) was determined. Histone H1b was present in the chromatin of liver, but not in the chromatin of hepatocellular carcinoma, testis or erythrocyte. Nuclease-resistant regions of liver chromatin had elevated levels of histone H1b. Histone H1b was isolated, and the N-terminal amino acid sequence of histone H1b was found to be highly similar to that of mammalian histone H1(0) and duck H5. HMG proteins T1, T2, T3, H6, C, D and F were associated with liver and hepatocellular-carcinoma chromatin, with hepatocellular carcinoma containing higher levels of HMG T1 and F. Testis and erythrocyte had HMG T2 and H6 as their predominant HMG proteins. Most of the HMG H6 of hepatocellular carcinoma, but not of liver, was located in a chromatin fraction that was soluble at physiological ionic strength and enriched in transcriptionally active DNA. These alterations in the chromatin distribution and content of hepatocyte HMG proteins and H1 histone subtypes may contribute to aberrant hepatocyte gene expression in the hepatocellular carcinoma.

Amino Acid Sequence↗
PubMed1972

Blocking by histones of accessibility to DNA in chromatin: addition of histones.

The blocking effect of histones on accessibility of DNA to DNase has been studied by addition of various histones to chromatin in intact or histone-depleted thymus nuclei (those from which all lysine-rich histone was removed and those from which much of the arginine-rich histone was removed) and to deoxyribonucleoprotein (chromatin) extracted from nuclei. In each case lysine-rich histone, weight for weight, blocks accessibility more effectively than does arginine-rich histone. Fractions of the arginine-rich histone differ considerably from each other in their blocking efficacy. Phosphorylation of lysine-rich histone tempers its blocking effectiveness.

Animals↗
PubMed1982

Analysis of histone gene expression during the cell cycle in HeLa cells by using cloned human histone genes.

Although it is generally agreed that histone protein synthesis is restricted to the S phase of the cell cycle--and therefore parallels DNA replication--both transcriptional and posttranscriptional levels of control have been invoked. Using blot hybridization with several cloned genomic human histone sequences representing different histone gene clusters as probes, we have assessed the steady-state level of histone RNAs in the nucleus and cytoplasm of G1 and S phase HeLa S3 cells. The representation of histone mRNA sequences of G1 compared with S phase cells was less than 1% in the cytoplasm and approximately 1% in the nucleus. These data are consistent with transcriptional control, but we cannot completely dismiss the possibility that regulation of histone gene expression is, to some extent, mediated posttranscriptionally. If histone gene transcription does occur in G1, the RNAs must either be rapidly degraded or be transcribed to a limited extent compared with S phase. An unexpected result was obtained when a blot of cytoplasmic RNA from G1 and S phase cells was hybridized with lambda HHG 41 DNA (containing H3 and H4 human genomic histone sequences). Although hybridization with histone mRNAs was observed for RNAs from S phase but not from G1 cells, hybridization with a nonhistone RNA of approximately 330 nucleotides present predominantly in G1 was also observed.

Bacteriophage lambda↗
PubMed1994

Contacts of the globular domain of histone H5 and core histones with DNA in a "chromatosome".

The globular domain of histone H5 is found to asymmetrically associate with a nucleosome core including the Xenopus borealis somatic 5S RNA gene. Histones H2A and H2B are required for association of histone H5. Strong crosslinking of the globular domain of histone H5 to the 5S DNA in the nucleosome occurs at a single site to one side of the dyad axis. This site is also in contact with the core histones, and the interactions of the core histones with 5S DNA change as a result of association of the globular domain of histone H5. We discuss evidence for an allosteric change in core histone-5S DNA interactions following the association of the linker histone in the nucleosome.

Animals↗
PubMed1990

The topoisomerase II inhibitor VM-26 induces marked changes in histone H1 kinase activity, histones H1 and H3 phosphorylation, and chromosome condensation in G2 phase and mitotic BHK cells.

We have examined the effects of topoisomerase inhibitors on the phosphorylation of histones in chromatin during the G2 and the M phases of the cell cycle. Throughout the G2 phase of BHK cells, addition of the topoisomerase II inhibitor VM-26 prevented histone H1 phosphorylation, accompanied by the inhibition of intracellular histone H1 kinase activity. However, VM-26 had no inhibitory effect on the activity of the kinase in vitro, suggesting an indirect influence on histone H1 kinase activity. Entry into mitosis was also prevented, as monitored by the absence of nuclear lamina depolymerization, chromosome condensation, and histone H3 phosphorylation. In contrast, the topoisomerase I inhibitor, camptothecin, inhibited histone H1 phosphorylation and entry into mitosis only when applied at early G2. In cells that were arrested in mitosis, VM-26 induced dephosphorylation of histones H1 and H3, DNA breaks, and partial chromosome decondensation. These changes in chromatin parameters probably reverse the process of chromosome condensation, unfolding condensed regions to permit the repair of strand breaks in the DNA that were induced by VM-26. The involvement of growth-associated histone H1 kinase in these processes raises the possibility that the cell detects breaks in the DNA through their effects on the state of DNA supercoiling in constrained domains or loops. It would appear that histone H1 kinase and topoisomerase II work coordinately in both chromosome condensation and decondensation, and that this process participates in the VM-26-induced G2 arrest of the cell.

Animals↗
PubMed2001

The N-terminus of histone H2B, but not that of histone H3 or its phosphorylation, is essential for chromosome condensation.

We have studied the role of individual histone N-termini and the phosphorylation of histone H3 in chromosome condensation. Nucleosomes, reconstituted with histone octamers containing different combinations of recombinant full-length and tailless histones, were used as competitors for chromosome assembly in Xenopus egg extracts. Nucleosomes reconstituted with intact octamers inhibited chromosome condensation as efficiently as the native ones, while tailless nucleosomes were unable to affect this process. Importantly, the addition to the extract of particles containing only intact histone H2B strongly interfered with chromosome formation while such an effect was not observed with particles lacking the N-terminal tail of H2B. This demonstrates that the inhibition effect observed in the presence of competitor nucleosomes is mainly due to the N-terminus of this histone, which, therefore, is essential for chromosome condensation. Nucleosomes in which all histones but H3 were tailless did not impede chromosome formation. In addition, when competitor nucleosome particles were reconstituted with full-length H2A, H2B and H4 and histone H3 mutated at the phosphorylable serine 10 or serine 28, their inhibiting efficiency was identical to that of the native particles. Hence, the tail of H3, whether intact or phosphorylated, is not important for chromosome condensation. A novel hypothesis, termed 'the ready production label' was suggested to explain the role of histone H3 phosphorylation during cell division.

Animals↗
PubMed1987

Postsynthetic acetylation of histones during the cell cycle: a general function for the displacement of histones during chromatin rearrangements.

Postsynthetic acetylation of core histones exhibits a peak during S-phase of the Physarum cell cycle. The maximum 3H-acetate incorporation precedes the maximum of histone synthesis. Acetate is incorporated into all core histones during S-phase, but only into H2A and H2B during G2-period. Resolution of acetylated H4-subspecies reveals acetate incorporation into preexisting H4, but not into newly synthesized molecules during mitosis and early S-phase. In a protamine competition assay histones from S-phase chromatin are released at lower protamine concentrations as compared to the lower acetylated G2-chromatin. We demonstrate a preferential release of highly acetylated H4-subspecies at low protamine concentrations. Our results fit into a general model of the relationship between histone acetylation and chromatin assembly. According to this model acetylation of core histones would serve as a signal for displacement of histones from nucleosomes by modulating histone-protein or histone-DNA interactions. We propose that this mechanism operates during DNA-replication and transcription, as well as during other chromatin rearrangements.

Acetates↗
PubMed2004

SLBP is associated with histone mRNA on polyribosomes as a component of the histone mRNP.

The stem-loop binding protein (SLBP) binds the 3' end of histone mRNA and is present both in nucleus, and in the cytoplasm on the polyribosomes. SLBP participates in the processing of the histone pre-mRNA and in translation of the mature message. Histone mRNAs are rapidly degraded when cells are treated with inhibitors of DNA replication and are stabilized by inhibitors of translation, resulting in an increase in histone mRNA levels. Here, we show that SLBP is a component of the histone messenger ribonucleoprotein particle (mRNP). Histone mRNA from polyribosomes is immunoprecipitated with anti-SLBP. Most of the SLBP in cycloheximide-treated cells is present on polyribosomes as a result of continued synthesis and transport of the histone mRNP to the cytoplasm. When cells are treated with inhibitors of DNA replication, histone mRNAs are rapidly degraded but SLBP levels remain constant and SLBP is relocalized to the nucleus. SLBP remains active both in RNA binding and histone pre-mRNA processing when DNA replication is inhibited.

Animals↗
PubMed2006

Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications.

Covalent histone post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitylation play pivotal roles in regulating many cellular processes, including transcription, response to DNA damage, and epigenetic control. Although positive-acting post-translational modifications have been studied in Saccharomyces cerevisiae, histone modifications that are associated with transcriptional repression have not been shown to occur in this yeast. Here, we provide evidence that histone sumoylation negatively regulates transcription in S. cerevisiae. We show that all four core histones are sumoylated and identify specific sites of sumoylation in histones H2A, H2B, and H4. We demonstrate that histone sumoylation sites are involved directly in transcriptional repression. Further, while histone sumoylation occurs at all loci tested throughout the genome, slightly higher levels occur proximal to telomeres. We observe a dynamic interplay between histone sumoylation and either acetylation or ubiquitylation, where sumoylation serves as a potential block to these activating modifications. These results indicate that sumoylation is the first negative histone modification to be identified in S. cerevisiae and further suggest that sumoylation may serve as a general dynamic mark to oppose transcription.

Acetylation↗
PubMed1983

Histone gene expression in early development of Xenopus laevis. Analysis of histone mRNA in oocytes and embryos by blot-hybridization and cell-free translation.

This study comprises the hybridization analysis of electrophoretically separated histone mRNAs from oocytes and embryos of Xenopus laevis, and analysis of in vitro translation products of these mRNAs on polyacrylamide gels containing sodium dodecyl sulfate (SDS) or Triton X-100. In oocytes and embryos up to the tailbud stage, four types of mRNAs complementary to histone H2B DNA and two complementary to histone H4 DNA can be discriminated by their different electrophoretic mobilities on polyacrylamide gels. Electrophoretic heterogeneity was not detected for messengers for histones H2A and H3. Histone mRNA, purified by hybridization under stringent conditions with a cloned histone gene cluster, was used to direct histone protein synthesis in a wheat-germ cell free system. The proteins synthesized comigrate with purified marker histones when electrophoresed on SDS-gels or acid-urea gels containing Triton X-100. When hybrid-selected histone mRNAs from oocytes and embryos in different developmental stages are translated, the proteins made by the mRNA from one stage can not be discriminated from those made by the mRNA from another stage after electrophoresis on SDS-gels or acid urea Triton X-100 gels.

Animals↗
PubMed2006

Displacement of histones at promoters of Saccharomyces cerevisiae heat shock genes is differentially associated with histone H3 acetylation.

Chromatin remodeling at promoters of activated genes spans from mild histone modifications to outright displacement of nucleosomes in trans. Factors affecting these events are not always clear. Our results indicate that histone H3 acetylation associated with histone displacement differs drastically even between promoters of such closely related heat shock genes as HSP12, SSA4, and HSP82. The HSP12 promoter, with the highest level of histone displacement, showed the highest level of H3 acetylation, while the SSA4 promoter, with a lower histone displacement, showed only modest H3 acetylation. Moreover, for the HSP12 promoter, the level of acetylated H3 is temporarily increased prior to nucleosome departure. Individual promoters in strains expressing truncated versions of heat shock factor (HSF) showed that deletion of either one of two activating regions in HSF led to the diminished histone displacement and correspondingly lower H3 acetylation. The deletion of both regions simultaneously severely decreased histone displacement for all promoters tested, showing the dependence of these processes on HSF. The level of histone H3 acetylation at individual promoters in strains expressing truncated HSF also correlated with the extent of histone displacement. The beginning of chromatin remodeling coincides with the polymerase II loading on heat shock gene promoters and is regulated either by HSF binding or activation of preloaded HSF.

Acetylation↗
PubMed1997

The five cleavage-stage (CS) histones of the sea urchin are encoded by a maternally expressed family of replacement histone genes: functional equivalence of the CS H1 and frog H1M (B4) proteins.

The cleavage-stage (CS) histones of the sea urchin are known to be maternally expressed in the egg, have been implicated in chromatin remodeling of the male pronucleus following fertilization, and are the only histone variants present in embryonic chromatin up to the four-cell stage. With the help of partial peptide sequence information, we have isolated and identified CS H1, H2A, H2B, H3, and H4 cDNAs from egg poly(A)+ mRNA of the sea urchin Psammechinus miliaris. All five CS proteins correspond to replacement histone variants which are encoded by replication-independent genes containing introns, poly(A) addition signals, and long nontranslated sequences. Transcripts of the CS histone genes could be detected only during oogenesis and in development up to the early blastula stage. The CS proteins, with the exception of H4, are unique histones which are distantly related in sequence to the early, late, and sperm histone subtypes of the sea urchin. In contrast, the CS H1 protein displays highest sequence homology with the H1M (B4) histone of Xenopus laevis. Both H1 proteins are replacement histone variants with very similar developmental expression profiles in their respective species, thus indicating that the frog H1M (B4) gene is a vertebrate homolog of the CS H1 gene. These data furthermore suggest that the CS histones are of ancient evolutionary origin and may perform similar conserved functions during oogenesis and early development in different species.

Amino Acid Sequence↗
PubMed1981

Histone-mediated agglutination of epididymal spermatozoa and the occurrence of histone receptors on the rat sperm surface.

Exogenous calf thymus whole histones showed a high degree of specificity to cause agglutination of rat epididymal spermatozoa. Histones had markedly greater (approximately 5-fold) agglutination activity than did salmon protamine whereas a variety of proteins, including strongly basic ones such as herring protamine sulphate, ribonuclease, cytochrome C and lysozyme, had no detectable agglutination activity. Histones F-3 and F-2a had the greatest activity for cell agglutination. Polyamines (5 mM), sialic acid (5 mM) and basic or acidic amino acids (10 mM) had no effect on histone (approximately 8 microM)-mediated sperm agglutination. 32P-Labelled histones showed a high specificity for binding to intact spermatozoa. The binding was saturable at a histone concentration of approximately 0.3 mg/ml and nearly completely displaced at saturating concentrations of native histones. Only unlabelled protamines competed to a small extent for binding of 32P-labelled histones to spermatozoa. The data are consistent with the view that histones bind specifically to sperm surface receptor sites before agglutination of cells.

Animals↗
PubMed1995

Effect of histone and histone-RNA complexes on the disease process of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterised by the production of a variety of autoantibodies against cell surface, nuclear and cytoplasmic antigens. The antigen or antigens responsible for the induction of this disease is/are unknown. We have analysed the antigenicity and pathogenicity of free histones and histones complexed with RNA in Balb/c, B10 Br, C57BL/6 and MRL-lpr/lpr mice by giving 1 microgram and 25 micrograms of each antigen intraperitoneally in complete and incomplete Freund's adjuvant. The same number of control animals were injected with either adjuvant or PBS. In the initial experiment we gave three doses of antigen at three weekly intervals. B10 Brown and C57BL/6 mice had no response to the antigens. Balb/c mice developed a mild transient antibody response against H1 histone, branched peptide of ubiquitinated H2A (peptide T4) and also against ssDNA. However in repeated experiments when the histone-RNA complex was injected into young MRL-lpr/lpr animals at two weekly intervals, a significantly increased antibody response was detected against H1, peptide T4 and some histone peptide residues (204-218 of H1, 1-20 and 65-85 of H2A, 1-25 of H2B, 1-21 of H3 and 1-29 of H4) compared to the control groups. Moreover, this group also showed elevated serum anti-DNA antibody levels and early impairment of renal function assessed by the urine protein levels. These experiments have demonstrated that there is a genetic variation in antibody responses against histones and histone-RNA complexes and that histone-RNA complexes exaggerate the disease in young MRL-lpr/lpr mice by inducing antibodies to basic regions of histones and other autoantigens.

Animals↗
PubMed1977

Studies of human histone messenger RNA. II. The resolution of fractions containing individual human histone messenger RNA species.

Polyribosomal 4 to 18 S RNA from S phase HeLa S-3 cells has been fractionated by chromatography on oligo(dT)-cellulose and resolved into multiple discrete components by continuous elution preparation electrophoresis. The human histone messenger RNA (mRNA) species associated with various polyadenylated [poly(A(+))] and nonpolyadenylated [poly(A(-))] components of 4 to 18 S RNA were determined by translation of these RNA fractions in vitro using a Krebs II ascites cell-free system followed by resolution of histones synthesized in vitro on polyacrylamide gels containing Triton X-100. The results of these studies indicate that poly(A(-)) 4 to 18 S RNA from S phase HeLa polyribosomes contains: (a) large quantities of discrete 7.4 and 8 S RNA species which are not functional histone mRNA; (b) a discrete 8.6 S RNA fraction which contains the templates of human histone H4; (c) 9.2 to 10.7 S RNA which contains mixtures of incompletely resolved histone H2B, H2A, and H3 mRNA (These mRNA species do not closely correspond to discrete RNA subfractions resolvable by our techniques.); (d) discrete 12 and 13 S RNA fractions which contain templates of human histone H1 polypeptides. The present studies also indicate that the mRNA templates of histone variants H3.2 and H3.3 have a slightly lower electrophoretic mobility than H3.1 mRNA and that H2A.2 mRNA has a slightly lower electrophoretic mobility than H2A.1 mRNA. In addition, appreciable quantities of H3.2, H3.3, and H2A.2 mRNA are bound to oligo(dT)-cellulose in 0.5 M KCl. These results indicate that mRNA species of the same histone class differ slightly in primary structure and are consistent with the hypothesis that some histone mRNA species contain short tracts of poly(A).

Chromatography, Affinity↗
PubMed1996

The major cytoplasmic histone acetyltransferase in yeast: links to chromatin replication and histone metabolism.

We have isolated the predominant cytoplasmic histone acetyltransferase activity from Saccharomyces cerevisiae. This enzyme acetylates the lysine at residue 12 of free histone H4 but does not modify histone H4 when packaged in chromatin. The activity contains two proteins, Hat1p and Hat2p. Hat1p is the catalytic subunit of the histone acetyltransferase and has an intrinsic substrate specificity that modifies lysine in the recognition sequence GXGKXG. The specificity of the enzyme in the yeast cytoplasm is restricted relative to recombinant Hat1p suggesting that it is negatively regulated in vivo. Hat2p, which is required for high affinity binding of the acetyltransferase to histone H4, is highly related to Rbap48, which is a subunit of the chromatin assembly factor, CAF-1, and copurifies with the human histone deacetylase HD1. We propose that the Hat2p/Rbap48 family serve as escorts of histone metabolism enzymes to facilitate their interaction with histone H4.

Acetylation↗
PubMed2005

Sequence specificity and role of proximal amino acids of the histone H3 tail on catalysis of murine G9A lysine 9 histone H3 methyltransferase.

The activity of recombinant murine G9a toward lysine 9 of histone H3 was investigated. GST fusion proteins containing various lengths of the histone H3 amino-terminal tail were used as substrates in the presence of recombinant G9a enzyme and AdoMet cosubstrate. The minimal substrate methylated by G9a contained seven amino acids (TARKSTG) of the histone H3 tail. Furthermore, mutational analysis of the minimal substrate was performed to identify the amino acids essential for G9a-mediated methylation. All amino acids except Thr-11 were indispensable for the methylation reaction. Steady-state kinetic analysis of the wild-type and histone H3 point mutants, lysine 4 changed to alanine (K4A) or lysine 27 changed to alanine (K27A), with purified G9a revealed similar catalytic efficiency but a reduction in turnover number (k(cat)) from 78 to 58 h(-)(1). G9a methylated synthetic peptide substrates containing the first 13 amino acids of histone H3 efficiently, although methylation, acetylation, or mutation of proximal Lys-4 amino acids reduced Lys-9 methylation. The k(cat) for wild-type peptide substrate vs Lys-4 acetyl- or trimethyl-modified peptide were 88 and 32 h(-)(1), respectively, and the K(m) for the peptides varied from 0.6 to 2.2 muM, resulting in a large difference (15-91) in catalytic efficiency. Ser-10 or Thr-11 phosphorylation resulted in poor methylation by G9a. Immunoprecipitation of unmodified and Ser-10 and Thr-11 phosphorylated histone H3 displayed mostly Lys-4 dimethylation. Dimethylated Lys-9 was reduced in Ser-10 and Thr-11 immunoprecipitated phosphorylated histones as compared to nonphosphorylated H3. In an immunocytochemical assay, GFP fusion SUV39H1 or G9a did not colocalize with phosphorylated histone H3. Thus, Ser-10/Thr-11 phosphorylation impairs Lys-9 methylation. These data suggest that the sequence context of the modified residue affects G9a activity and the modification in the proximal amino acids influences methylation.

Amino Acid Sequence↗
PubMed2001

Histone hyperacetylation induced by histone deacetylase inhibitors is not sufficient to cause growth inhibition in human dermal fibroblasts.

Use of specific histone deacetylase inhibitors has revealed critical roles for the histone deacetylases (HDAC) in controlling proliferation. Although many studies have correlated the function of HDAC inhibitors with the hyperacetylation of histones, few studies have specifically addressed whether the accumulation of acetylated histones, caused by HDAC inhibitor treatment, is responsible for growth inhibition. In the present study we show that HDAC inhibitors cause growth inhibition in normal and transformed keratinocytes but not in normal dermal fibroblasts. This was despite the observation that the HDAC inhibitor, suberic bishydroxamate (SBHA), caused a kinetically similar accumulation of hyperacetylated histones. This cell type-specific response to SBHA was not due to the inactivation of SBHA by fibroblasts, nor was it due to differences in the expression of specific HDAC family members. Remarkably, overexpression of HDACs 1, 4, and 6 in normal human fibroblasts resulted in cells that could be growth-inhibited by SBHA. These data suggest that, although histone acetylation is a major target for HDAC inhibitors, the accumulation of hyperacetylated histones is not sufficient to cause growth inhibition in all cell types. This suggests that growth inhibition, caused by HDAC inhibitors, may be the culmination of histone hyperacetylation acting in concert with other growth regulatory pathways.

Acetylation↗