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PubMed2006

Histones and histone modifications in protozoan parasites.

Protozoan parasites are early branching eukaryotes causing significant morbidity and mortality in humans and livestock. Single-celled parasites have evolved complex life cycles, which may involve multiple host organisms, and strategies to evade host immune responses. Consequently, two key aspects of virulence that underlie pathogenesis are parasite differentiation and antigenic variation, both of which require changes in the expressed genome. Complicating these requisite alterations in the parasite transcriptome is chromatin, which serves as a formidable barrier to DNA processes including transcription, repair, replication and recombination. Considerable progress has been made in the study of chromatin dynamics in other eukaryotes, and there is much to be gained in extending these analyses to protozoan parasites. Much of the work completed to date has focused on histone acetylation and methylation in the apicomplexans and trypanosomatids. As we describe in this review, such studies provide a unique vantage point of the evolutionary picture of eukaryotic cell development, and reveal unique phenomena that could be exploited pharmacologically to treat protozoal diseases.

Acetylation↗
PubMed1980

Effects of acetic acid-alcohol, trypsin, histone 1 and histone fragments on Giemsa staining patterns in chromosomes.

In an effort to minimize subjective bias, a classification scheme was devised to assess Giemsa staining patterns obtained with experiments involving acetic acid-alcohol and exogenously applied histone 1 and polypeptides. A single rinse of metaphase preparations with acetic acid-alcohol quantitatively reduced Giemsa dye binding. Acid-alcohol irreversibly changed the conformation of H1 and its ability to interfere with trypsin G-banding. Our results suggest that, in addition to protein extraction, acid-alcohol may alter the conformation of acid-insoluble components of metaphase chromosomes. The carboxy-terminal polypeptide (residues 73--212) from NBS cleavage of H1 was an effective inhibitor of Giemsa staining and trypsin G-banding. However, this polypeptide which is preferential for supercoiled DNA was much less efficient in inhibiting Giemsa staining of trypsinized metaphase chromosomes. The molecular consequences of these experiments are discussed.

Acetates↗
PubMed1985

Core histone variants and ubiquitinated histones 2A and 2B of rat cerebral cortex neurons.

The pattern of non-allelic variants of core histones was investigated in terminally differentiated rat cerebral cortex neurons. At 30 days two major H2A variants are present, H2A.1 and .2, together with two minor components, .x and .z. H2B has two variants, H2B.1 and .2, and H3 presents three variants, H3.1, .2 and .3. The ubiquitinated adducts of all H2A and H2B variants can be recognised on two-dimensional electrophoresis as forming a pattern similar to that of the unmodified species. uH2A amounts to 12-14% of total H2A. All H2A variants appear to be equally modified. uH2B amounts to 1-2% of total H2B.

Animals↗
PubMed1987

Spectroscopic studies on histone-DNA interactions. I. The interaction of histone (H2A, H2B) dimer with DNA: DNA sequence dependence.

Binding of the histone (H2A, H2B) dimer with chicken erythrocyte DNA has been studied by salt-titration spectroscopy in equilibrium conditions. The circular dichroism of DNA near 275 nm is depressed by the interaction with (H2A, H2B) at low concentrations of salt. The depression increases with increasing amounts of (H2A, H2B), and reaches a plateau at an (H2A, H2B) to DNA ratio of 1.5 (w/w), at which one (H2A, H2B) dimer occupies 28 base-pairs of DNA. The fluorescence emission intensity of the tyrosine residues in (H2A, H2B) is depressed by the H2A, H2B)-DNA interaction. When the DNA-(H2A, H2B) complex is titrated with NaCl, these two signals show transitions with increasing ionic strength of the buffer, whose normalized transition curves agree well. The midpoint of the transition is about 0.42 M-NaCl for a sample with a DNA concentration of 0.05 mg/ml and an (H2A, H2B) to DNA ratio of 0.4 (w/w). The fluorescence titration curves have been analyzed to obtain the binding constant for the (H2A, H2B) dimer with DNA. The sample concentration dependence of the titration profiles is consistent with the model of non-cooperative binding of (H2A, H2B) dimer to DNA. The titration profiles are reversible. The obtained binding constant for the (H2A, H2B) dimer with chicken erythrocyte DNA at 20 degrees C (pH 7.6), as a function of the ionic strength, I, is as follows: log10K = -14.9 log10(I)-1.2. The change of enthalpy delta H accompanied by the binding of the (H2A, H2B) dimer is nearly equal to zero, within an error of +/- 1.4 kcal/mol (1 cal = 4.184 J). DNA sequence dependence of the stability of DNA-(H2A, H2B) interactions is observed using reconstituted materials of synthetic DNAs. A decreasing stability of the interaction is observed following the order: the duplex of poly[(dA)-(dT)] greater than chicken erythrocyte DNA or the copolymer duplex of poly(dA).poly(dT) greater than the duplex of poly[(dG)-(dC)]. The difference in free energy of the association of the (H2A,H2B) dimer between the two copolymers is 0.8 kcal/mol.

Animals↗
PubMed1986

Use of double spin-labeled histones to monitor histone-chromatin integration.

Tyrosine-specific nitroxide spin labels have been synthesized that utilize either deuterium or deuterium and [15N] isotopic substitution within the nitroxide ring. These probes have been used to differentially spin label and simultaneously monitor both histones H1 and H5, during the displacement of endogenous spin-labeled H1 from reconstituted chromatin by exogenously added spin-labeled H5.

Animals↗
PubMed1977

Phosphorylation and dephosphorylation of histone (V (H5): controlled condensation of avian erythrocyte chromatin. Appendix: Phosphorylation and dephosphorylation of histone H5. II. Circular dichroic studies.

During avian erythropoiesis, the blast cells of the bone marrow mature into polychromatic erythrocytes (late stages knwon as reticulocytes) and then into mature red blood cells. When chickens are made anemic, the proportion of immature cells in the anemic bone marrow increases dramatically. The level of the lysine-rich histones. H1 and H5, has been found to be constant in the blood and bone marrow of normal and anemic chickens. This implies that H5 replaces H1 quantitatively. Urea-aluminum-lactate starch gel electrophoresis of H5 from these sources show that the degree of phosphorylation of H5 is proportional to the number of immature cells. About 70% of the H5 from the most immature bone marrow is phosphorylated, while 50% of the H5 from anemic blood is phosphorylated and H5 in normal blood is almost completely devoid of phosphate. When immature cells of the anemia bone marrow are incubated in the presence of inorganic 32P and [3H]lysine and [3H]arginine, extensive 32P incorporation is found in the phospho species. A minimum of nine phosphorylated components have been demonstrated by starch gel electrophoresis. The incorporation of 3H is time dependent. After 1.5 h of labeling, 3H is found in H5 containing 0, 1, 2, and 3 phosphates. tthe combined data suggest that newly synthesized H5 becomes progressively phosphorylated and that at the terminal stage of development, the phosphorylated H5 is completely dephosphorylated. These events may be important in controlling the timing of chromatin condensation.

Anemia↗
PubMed1975

Histone-histone associations within chromatin. Cross-linking studies using tetranitromethane.

Treatment of chromatin with the protein cross-linker tetranitromethane (TNM) results in a product identified as an F2a1-F2b dimer. The same product appears after treatment with TNM of HeLa cells growing in culture. Furthermore acid-extracted histones which have been fractionated into the five separate species can be recombined and mixed with DNA to produce a nucleohistone preparation which is also cross-linked by TNM to give the F2a1-F2b dimer. F1 and F3 can be excluded from the reconstitution mixture without effect on the dimer production. In contrast, the presence of F2a2 is essential to the proper reconstitution of F2a1 and F2b with DNA. The specificity of TNM and the characteristics of the reaction suggest that F2a1 and F2b are cross-linked at their specific binding sites. These results provide evidence that F2a1, F2a2, and F2b interact specifically in chromatin.

Animals↗
PubMed1996

Interactions of nickel(II) with histones: enhancement of 2'-deoxyguanosine oxidation by Ni(II) complexes with CH3CO-Cys-Ala-Ile-His-NH2, a putative metal binding sequence of histone H3.

Studies of 2'-deoxyguanosine oxidation by hydrogen peroxide in the presence of CH3CO-Cys-Ala-Ile-His-NH2 (CAIH) and/or NiCl2 have been carried out in 100 mM phosphate buffer (pH 7.4) at 37 degrees C. The dimeric CAIH oxidation product, CAIH disulfide, and its weak, octahedral Ni(II) complex, rather than the monomeric CAIH and its strong, square-planar Ni(II) complex, were found to be major catalysts of 8-oxo-2'-deoxyguanosine (8-oxo-dG) formation. The presence of Ni(II) largely enhanced 8-oxo-dG yield, especially at submillimolar concentrations of H2O2. The reaction was found not to involve detectable amounts of free radicals or Ni(III). These results, together with those published previously [Bal, W. et al. (1995) Chem. Res. Toxicol. 8, 683-692], lay a framework for the detailed investigations of the interactions of histone octamer with Ni(II) and other metal ions. They also suggest that molecular mechanisms of nickel carcinogenesis may involve oxidative damage processes catalyzed by weak Ni(II) complexes with cellular components.

DNA Adducts↗
PubMed2004

Invasion of v-Fos(FBR)-transformed cells is dependent upon histone deacetylase activity and suppression of histone deacetylase regulated genes.

Transformation of fibroblasts with the v-fos oncogene produces a highly invasive phenotype that is mediated by changes in gene expression. Inhibition of histone deacetylase (HDAC) activity with trichostatin A (TSA) or valproic acid (VPA) at concentrations that do not affect morphology, motility, chemotaxis or proliferation, strongly inhibits invasion and results in the re-expression of a significant proportion of those genes that are downregulated in the v-Fos-transformed cells. Independent expression of three of these re-expressed genes, (Ring1 and YY1 binding protein (RYBP); protocadherin gamma subfamily C,3 (PCDHGC3); and signal transducer and activator of transcription 6 (STAT6)) in Fos-transformed cells, has no effect on morphology, motility, chemotaxis or proliferation, but strongly inhibits invasion. Therefore, we conclude that the ability of v-Fos-transformed cells to invade is dependent upon repression of gene expression through either direct or indirect HDAC activity.

Actins↗
PubMed1979

The isolation and partial sequence of peptides produced by cyanogen bromide cleavage of calf thymus non-histone chromosomal high-mobility-group protein 2. Sequence homology with non-histone chromosomal high-mobility-group protein 1.

Peptides produced by CNBr cleavage of non-histone chromosomal protein HMG 2 (CNBr peptides) were isolated and characterized, and their partial sequences were determined. The present sequence data account for over half of the sequence of the protein HMG (high-mobility-group) 2 molecule, and, together with previously published results, provide interesting information on the charge distribution within the molecule. Comparison of the CNBr-peptide-sequence data for protein HMG 2 with the previously published data on the CNBr peptides from protein HMG 1 reveals extensive sequence homology between the two proteins. Detailed evidence for the amino acid-sequence data has been deposited as Supplementary Publication SUP 50095 (6 pages) at the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies may be obtained on the terms given in Biochem. J. (1978) 169, 5.

Amino Acid Sequence↗
PubMed2001

The basic helix-loop-helix protein, sharp-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism.

Many aspects of neurogenesis and neuronal differentiation are controlled by basic helix-loop-helix (bHLH) proteins. One such factor is SHARP-1, initially identified on the basis of its sequence similarity to hairy. Unlike hairy, and atypically for bHLHs, SHARP-1 is expressed late in development, suggestive of a role in terminal aspects of differentiation. Nevertheless, the role of SHARP-1 and the identity of its target genes remain unknown. During the course of a one-hybrid screen for transcription factors that bind to regulatory domains of the M1 muscarinic acetylcholine receptor gene, we isolated the bHLH transcription factor SHARP-1. In this study, we investigated the functional role of SHARP-1 in regulating transcription. Fusion proteins of SHARP-1 tethered to the gal4 DNA binding domain repress both basal and activated transcription when recruited to either a TATA-containing or a TATAless promoter. Furthermore, we identified two independent repression domains that operate via distinct mechanisms. Repression by a domain in the C terminus is sensitive to the histone deacetylase inhibitor trichostatin A, whereas repression by the bHLH domain is insensitive to TSA. Furthermore, overexpression of SHARP-1 represses transcription from the M(1) promoter. This study represents the first report to assign a function to, and to identify a target gene for, the bHLH transcription factor SHARP-1.

Amino Acid Sequence↗
PubMed1990

Labelling of histone H5 and its interaction with DNA. 1. Histone H5 labelling with fluorescein isothiocyanate.

Histone H5 has been labelled with fluorescein isothiocyanate (FITC) with particular attention to the reaction conditions (pH, reaction time and input FITC/H5 molar ratio) and to the complete elimination of non-covalently bound dye. We preferred to use reaction conditions which yielded non-specific uniform labelling rather than specific alpha-NH2 terminal labelling, in order to obtain higher sensitivity in further studies dealing with the detection of perturbation at the binding sites of H5 on DNA. FITC-labelled H5 was further characterized by absorption and circular dichroism spectroscopy, and the fluorescein probe titrated in the 4-8 pH range. The structural integrity of H5 was found to be preserved after labelling. The positive electrostatic potential of the environment in which the FITC probe is embedded in the arginine/lysine-rich tails of H5 is believed to be responsible for the drop of pK of 1 unit found for H5-FITC as compared to free FITC. For the globular part of H5, the pK of covalently-bound FITC was only slightly lowered; this is a consequence of the much lower content in positively-charged amino-acid side chains in this region.

Animals↗
PubMed1995

Association of histone H4 genes with the mammalian testis-specific H1t histone gene.

Mouse and human H4 genes associated with the testis-specific H1t gene were isolated from genomic libraries and were sequenced. The deduced amino acid sequences are identical to other mouse or human H4 histones, but the genes differ significantly in their nucleotide sequences. Both the human and the mouse genes are located on the same DNA strand compared with the H1t gene. In contrast to this identical transcriptional orientation of H1t and its neighboring H4 gene in mouse and man, an H4 gene with the opposite orientation has been described in the vicinity of the rat H1t gene. Northern blot analysis of RNA from testicular cells separated by centrifugal elutriation, S1 nuclease mapping, and reverse transcriptase polymerase chain reaction (RT-PCR) amplification show that both the murine and human H4 genes, like the H1t gene, are expressed in testicular cells, whereas the H4 genes, in contrast to the H1t gene, are expressed in nontesticular human and mouse cell culture cells.

Amino Acid Sequence↗
PubMed1982

In vitro recognition of DNA base pairs by histones in histone-DNA complexes and reconstituted core particles: an ultraviolet resonance Raman study.

Resonance Raman spectra of complexes between DNA and the four core histones, alone or associated, have been investigated in vitro using excitations at 300 and 257 nm, which give complementary informations about the DNA bases. H2A and H2B fractions recognize the G-C base pairs, while H3 and H4 (arginine rich fractions) recognize the A-T base pairs. The associated fractions form complexes with DNA which yield about the same DNA spectral modifications as the DNA-H4 complexes. This reveals the important role of the arginine rich fractions in the core particle formation and confirms the preferential in vitro assembly of nucleosome cores on A-T rich regions of DNA (25).

Animals↗
PubMed1987

Characterization of a cDNA clone coding for a sea urchin histone H2A variant related to the H2A.F/Z histone protein in vertebrates.

A cDNA clone coding for a sea urchin histone H2A variant has been isolated. The coding region of the clone has been sequenced and the sequence found to be closely related to the H2A.F sequence in chickens. The nucleotide sequence of the sea urchin H2A.F/Z is 74% conserved when compared to chicken H2A.F and 51% conserved compared to sea urchin H2A early and 60% compared to sea urchin H2A late. The nucleotide-derived amino acid comparisons show that H2A.F/Z is 97% homologous with H2A.F in chickens and 57% and 56% homologous when compared to sea urchin H2A early and late respectively. There are between 3-6 copies of the H2A.F/Z sequence in the S. purpuratus genome. The H2A.F/Z gene sequence codes for the previously identified H2A.Z protein. All embryonic stages and adult tissues tested contain mRNA for H2A.F/Z. The mRNA appears in the poly A+ RNA fraction after chromatography over oligo dT cellulose.

Age Factors↗
PubMed2003

Characterization of histone H2A.X expression in testis and specific labeling of germ cells at the commitment stage of meiosis with histone H2A.X promoter-enhanced green fluorescent protein transgene.

To study the complex molecular mechanisms of mammalian spermatogenesis, it would be useful to be able to isolate cells at each stage of differentiation, especially at the stage in which the cells switch from mitosis to meiosis. Currently, no useful marker proteins or gene promoters specific to this important stage are known. We report here a transgenic mouse line that under the control of the promoter for a histone variant, H2A.X, expressed an enhanced green fluorescent protein (EGFP) in cells at the stage of the mitosis-meiosis switch. Endogenous H2A.X is expressed in type A spermatogonia through meiotic prophase spermatocytes in testis and in some somatic cells. However, despite the fact that its expression was driven by the H2A.X promoter, the EGFP expressed in the transgenic mice specifically labeled only the intermediate spermatogonia stage through the meiotic prophase spermatocyte stage in transgenic mice containing the -600-base pair H2A.X promoter/EGFP construct. Type A spermatogonia and somatic cells of other organs were not labeled. This expression pattern made it possible to isolate living cells from the testis of the transgenic mice at the stage of the mitosis-meiosis switch in spermatogenesis using EGFP fluorescence.

Animals↗
PubMed1975

Studies on the role and mode of operation of the very-lysine-rich histone H1 (F1) in eukaryote chromatin. The properties of the N-terminal and C-terminal halves of histone H1.

Restricted chymotrypsin digestion of calf thymus H1 histone gives two fragments, residues 1--106 and 107--C-terminal. These were studied by proton magnetic resonance and circular dichroism. The N-terminal fragment exhibited some salt-induced structure in aqueous solution, but this did not parallel the globular structure of the intact H1 molecule. Comparison of circular dichroism results with helix predictions for this portion of the molecule suggests that the secondary structure may be the same in this fragment as it is in the corresponding region of the whole molecule. The C-terminal fragments show very little salt-induced structure. The N-terminal fragments binds to DNA very weakly, but the C-terminal fragment binds as strongly as the whole molecule. In the C-terminal fragment, about one quarter of the lysine residues are not bound to the DNA in water, but initial increase of salt concentration causes them to become bound. This increasing binding occurs under the same ionic conditions that cause chromatin condensation and condensation of H1 - DNA complexes, and it is suggested that there may be a connection between these phenomena.

Amino Acids↗