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PubMed1998

HAT1 and HAT2 proteins are components of a yeast nuclear histone acetyltransferase enzyme specific for free histone H4.

We have analyzed the histone acetyltransferase enzymes obtained from a series of yeast hat1, hat2, and gcn5 single mutants and hat1,hat2 and hat1,gcn5 double mutants. Extracts prepared from both hat1 and hat2 mutant strains specifically lack the following two histone acetyltransferase activities: the well known cytoplasmic type B enzyme and a free histone H4-specific histone acetyltransferase located in the nucleus. The catalytic subunits of both cytoplasmic and nuclear enzymes have identical molecular masses (42 kDa), the same as that of HAT1. However, the cytoplasmic complex has a molecular mass (150 kDa) greater than that of the nuclear complex (110 kDa). The possible functions of HAT1 and HAT2 in the yeast nucleus are discussed. In addition, we have detected a yeast histone acetyltransferase not previously described, designated HAT-A4. This enzyme is located in the nucleus and is able to acetylate free and nucleosome-bound histones H3 and H4. Finally, we show that the hat1, gcn5 double mutant is viable and does not exhibit a new phenotype, thus suggesting the existence of several histone acetyltransferases with overlapping functions.

Acetylation↗
PubMed2002

Dynamics of global histone acetylation and deacetylation in vivo: rapid restoration of normal histone acetylation status upon removal of activators and repressors.

DNA-binding activators and repressors recruit histone acetylases and deacetylases to promoters, thereby generating localized domains of modified histones that influence transcriptional activity. At the end of a transcriptional response, alterations in histone acetylation status are reversed, but the dynamics of this process are poorly understood. Here, we recruit histone deacetylases and acetylases to a well-defined yeast promoter in a regulated manner. Following dissociation of the recruiting protein from the promoter, targeted deacetylation and acetylation are reversed with rapid, yet distinct, kinetics. Reversal of targeted deacetylation occurs within 5-8 min, whereas reversal of targeted acetylation is more rapid, taking 1.5 min. These findings imply that untargeted, globally acting enzymes generate a highly dynamic equilibrium of histone acetylation and deacetylation reactions across chromatin. Targeted acetylases and deacetylases can locally perturb this equilibrium, yet once they are removed, the global activities mediate a rapid return to the steady-state level of histone acetylation. Our results also indicate that TBP occupancy depends on the presence of the activator, not histone acetylation status.

Acetylation↗
PubMed2025

The Expanding Histone Universe: Histone-Based DNA Organization in Noneukaryotic Organisms.

Histones are small basic proteins that form the proteinaceous core of the nucleosome, the repeating building block of chromatin in all eukaryotes. Long thought to be exclusive to eukaryotes, histones are now increasingly appreciated for their roles in organizing genomes across all domains of life, namely in archaea, bacteria, and even viruses. We survey recent advances in our understanding of the imaginative uses of histones in disparate biological entities, ranging from nucleosome-like metastable particles in giant viruses to slinky-like hypernucleosomes in archaea to bacterial histones that bind DNA in decidedly unorthodox ways. Across these different contexts, we examine how DNA compaction and conformation emanate from evolutionarily conserved aspects of histone structure, including how the oligomeric states of histones dictate their capacity to contort DNA in different conformations. It appears that relatively small tweaks to the amino acid sequences of histones can result in structural and functional variations in DNA binding. As such, nucleosomes in eukaryotes sample only a narrow range of possible structures.

Histones↗
PubMed2004

Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation.

PURPOSE: Histone deacetylase (HDAC) inhibitors are undergoing clinical evaluation in cancer therapy. Because HDAC modulation has been shown to enhance the radiosensitivity of tumor cells in vitro, we investigated the effects of the HDAC inhibitor MS-275 on the radioresponse of DU145 prostate carcinoma xenografts. EXPERIMENTAL DESIGN: As an indicator of HDAC inhibition in vivo, the histone acetylation status in tumor lysates was determined after two, four, and six injections of MS-275 delivered at 12-hour intervals, as well as 24 and 48 hours after the last injection. Tumor growth delay studies were then performed using this DU-145 xenograft model with radiation administered to leg tumors after the fourth dose of MS-275, which corresponded to the time of maximum histone hyperacetylation. RESULTS: An increase in histone hyperacetylation was detected in each tumor after two injections of MS-275 with a maximum hyperacetylation occurring after four to six injections. In tumor growth delay studies, the combination of MS-275 and radiation resulted in a greater than additive inhibition of tumor growth as compared with the individual modalities. As alternative sources for an indicator of drug radiosensitizing activity, histone hyperacetylation was determined in a series of normal tissues, including lymphocytes. Each of the normal tissues also had a maximal histone hyperacetylation after four to six injections of MS-275. CONCLUSIONS: These studies show that MS-275 enhances the radiosensitivity of DU145 xenografts and suggest that histone hyperacetylation status can serve as a useful marker for drug radiosensitizing activity.

Acetylation↗
PubMed2006

Sequential phosphorylation of Ser-10 on histone H3 and ser-139 on histone H2AX and ATM activation during premature chromosome condensation: relationship to cell-cycle phase and apoptosis.

BACKGROUND: Histone H1 and H3 phosphorylation associated with chromatin condensation during mitosis has been studied extensively. Less is known on histone modifications that occur during premature chromosome condensation (PCC). The aim of the present study was to reveal the status of histone H3 and H2AX phosphorylation on Ser-10 and Ser-139, respectively, as well as ATM activation through phosphorylation on Ser-1981, during PCC, and relate these events to cell-cycle phase and to initiation of apoptosis. MATERIALS AND METHODS: To induce PCC, A549 and HL-60 cells were exposed to the phosphatase inhibitor calyculin A (Cal A). Phosphorylation of histone H3 and H2AX as well as ATM activation were detected immunocytochemically concurrent with analysis of cellular DNA content and activation of caspase-3, a marker of apoptosis. The intensity of cellular fluorescence was measured by flow- or laser scanning cytometry. RESULTS: Induction of PCC led to rapid histone H3 phosphorylation, followed by activation of ATM and then H2AX phosphorylation in both, HL-60 and A549 cells. All these events occurred sequentially, prior to caspase-3 activation, and affected cells in all phases of the cell cycle. ATM activation and H2AX phosphorylation was seen during mitosis of A549 but not HL-60 cells. CONCLUSIONS: Because the Cal A-induced phosphorylation of histone H3 and H2AX, and of ATM, precede caspase-3 activation these modifications are pertinent to PCC and not to apoptosis-associated chromatin condensation. The sequence of histone H3 and H2AX phosphorylation and ATM activation during PCC is compatible with a role of ATM in mediating phosphorylation of H2AX but not H3. Mitosis in some cell types may proceed without ATM activation and H2AX phosphorylation.

Apoptosis↗
PubMed1990

Nucleosome assembly in vitro: separate histone transfer and synergistic interaction of native histone complexes purified from nuclei of Xenopus laevis oocytes.

High speed supernatants of Xenopus laevis oocyte nuclei efficiently assemble DNA into nucleosomes in vitro under physiological salt conditions. The assembly activity cofractionates with two histone complexes composed of the acidic protein N1/N2 in complex with histones H3 and H4, and nucleoplasmin in complex with histones H2B and H2A. Both histone complexes have been purified and their nucleosome assembly activities have been analysed separately and in combination. While the histones from the N1/N2 complexes are efficiently transferred to DNA and induce supercoils into relaxed circular plasmid DNA, the nucleoplasmin complexes show no supercoil induction, but can also transfer their histones to DNA. In combination, the complexes act synergistically in supercoil induction thereby increasing the velocity and the number of supercoils induced. Electron microscopic analysis of the reaction products shows fully packaged nucleoprotein structures with the typical nucleosomal appearance resulting in a compaction ratio of 2.8 under low ionic strength conditions. The high mobility group protein HMG-1, which is also present in the soluble nuclear homogenate from X. laevis oocytes, is not required for nucleosome core assembly. Fractionation experiments show that the synergistic effect in the supercoiling reaction can be exerted by histones H3 and H4 bound to DNA and the nucleoplasmin complexes alone. This indicates that it is not the synchronous action of both complexes which is required for nucleosome assembly, but that their cooperative action can be resolved into two steps: deposition of H3 and H4 from the N1/N2 complexes onto the DNA and completion of nucleosome core formation by addition of H2B and H2A from the nucleoplasmin complexes.

Animals↗
PubMed1991

Protein/DNA interactions involving ATF/AP1-, CCAAT-, and HiNF-D-related factors in the human H3-ST519 histone promoter: cross-competition with transcription regulatory sites in cell cycle controlled H4 and H1 histone genes.

Protein/DNA interactions of the H3-ST519 histone gene promoter were analyzed in vitro. Using several assays for sequence specificity, we established binding sites for ATF/AP1-, CCAAT-, and HiNF-D related DNA binding proteins. These binding sites correlate with two genomic protein/DNA interaction domains previously established for this gene. We show that each of these protein/DNA interactions has a counterpart in other histone genes: H3-ST519 and H4-F0108 histone genes interact with ATF- and HiNF-D related binding activities, whereas H3-ST519 and H1-FNC16 histone genes interact with the same CCAAT-box binding activity. These factors may function in regulatory coupling of the expression of different histone gene classes. We discuss these results within the context of established and putative protein/DNA interaction sites in mammalian histone genes. This model suggests that heterogeneous permutations of protein/DNA interaction elements, which involve both general and cell cycle regulated DNA binding proteins, may govern the cellular competency to express and coordinately control multiple distinct histone genes.

Activating Transcription Factors↗
PubMed1996

Histone H1 and core histones in Leishmania and Crithidia: comparison with Trypanosoma.

The Trypanosomatidae family is characterized by flagellated protozoa presenting a kinetoplast. Several genera of this family contain species that are pathogenic to man and domestic animals. Their chromatin is not condensed into chromosomes during cell division. As a contribution to the understanding of basic aspects of their genome organization, we present a systematic characterization of the histones from three genera of the Trypanosomatidae family. Crithidia fasciculata and Leishmania mexicana show core nucleosomal histones with electrophoretic mobilities both similar to and different from those of Trypanosoma cruzi and higher eukaryotes. Another protein is extracted from the chromatin of these organisms by procedures designed to purify histone H1. This protein presents elution profiles by HPLC and amino acid composition of histone H1. Considering these data and the high mobility of this protein in Triton-acetic acid-urea-polyacrylamide gel electrophoresis, as well as its position relative to the nucleosomal core histones in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we postulate that Crithidia and Leishmania possess a histone H1 shorter than that of higher eukaryotes as we have previously shown to be the case for T. cruzi. The possible presence of a shorter histone H1 in these trypanosomatids may explain the absence of chromatin condensation during cell division in these flagellates.

Amino Acids↗
PubMed2007

Developmentally regulated histone modifications in Drosophila follicle cells: initiation of gene amplification is associated with histone H3 and H4 hyperacetylation and H1 phosphorylation.

We have used gene amplification in Drosophila follicle cells as a model of metazoan DNA replication to address whether changes in histone modifications are associated with replication origin activation. We observe that replication initiation is associated with distinct histone modifications. Acetylated lysines K5, K8, and K12 on histone H4 and K14 on histone H3 are specifically enriched during replication initiation at the amplification origins. Strikingly, H4 acetylation persists at an amplification origin well after replication forks have progressed significantly outward from the origin, indicating that H4 acetylation is associated with origin regulation and not histone deposition at the replication forks. Origin recognition complex subunit 2 (orc2) mutants with severe amplification defects do not abolish H4 acetylation, whereas the dup/cdt1 mutant delays the appearance of acetylation foci, and mutants in rbf result in temporal persistence. These data indicate that core histone acetylation is associated with origin activity. Furthermore, follicle cells undergoing gene amplification exhibit high levels of histone H1 phosphorylation. The patterns of H1 phosphorylation provide insights into cell cycle states during amplification, as H1 kinase activity in follicle cells is responsive to high Cyclin E activity, and it can be abolished by overexpressing the retinoblastoma homolog, Rbf, that represses Cyclin E. These data suggest that amplification origins are able to initiate when the cells are in a late S-phase, when the genome is normally not licensed for replication.

Acetylation↗
PubMed1977

Interactions of histones and histone peptides with DNA Thermal denaturation and solubility studies.

The interactions of DNA with the five histone components (H1, H2B, H2A, H3 and H4) and with a number of histone fragments (N-H1 (1--72), C-H1 (73--216), N-H2B (l--59), C-H2B, (63--125), N-H2A (1-39), C-H2A (58--129), N-H4 (1--84) and C-H4 (85--102) have been studied by using the techniques of thermal denaturation and solubility behaviour. Complexes in 10(-3) M phosphate buffer, 2 - 10(-5) M Na(2)-EDTA, pH 7.0 were prepared by the direct mixing method. For lysine-rich histones (H1 and H2B) it has been found that the main characteristics which governs the interaction with DNA are located in the very lysine-rich part of the molecules, i.e. in the C-H1 and N-H2B segments. These regions are also responsible for a cooperative distribution of the histone along the DNA molecules in the artificial complexes. It appears from our studies that the tertiary structure of the moderately, arginine-rich histone (H2A) is an essential feature for its interaction with DNA. The two arginine-rich histones (H3 and H4) complexed with DNA behave in a similar way, both in thermal denaturation and in DNA precipitation. In the case of C-H4, a marked shift of the melting profile has been observed which is correlated with the presence in the peptide of the hydrophilic cluster Lys-Arg-Gln-Gly-Arg-Thr. Our results suggest that large segments rich in lysine and basic clustering within histones give rise to different modes of electrostatic interaction with DNA.

Animals↗
PubMed1979

Plant histone 2 from wheat germ, a family of histone H2a variants. Partial amino acid sequences.

1. The 0.5 M perchloric acid extract prepared from chromatin of wheat germ, Triticum aestivum, contains a group of histones formerly called plant histones. These can be resolved by gel filtration on Bio-Gel P-60 with subsequent CM-cellulose ion-exchange chromatography into five histone fractions containing families of histones H2A and H2B. 2. The partial amino acid sequences of histone H2A variants H2A(1)Triticum, H2A(2)Triticum and H2A(3)Triticum are presented. Extensive sequence homology exists between calf thymus histone H2A and wheat embryo H2A histones. Differences are largely due to conservative amino acid substitutions and in two of the variants, viz. H2A(2) and H2A(3) to N-terminal extensions of the polypeptide chains.

Amino Acid Sequence↗
PubMed1983

Histone H1 and chromatin higher order structure. Does histone H1 exhibit specific self-association?

1. Histones H1 and H5 in chromatin and in free solution can be cross-linked to higher multimers. Is this due to a specific protein/protein interaction? If so, this interaction might be the structural basis of the condensation of the chromosomal nucleofilament, known to be mediated by histones H1 and H5. 2. Since only the central domain of H1 and H5 exhibits tertiary folding and globular structure, this is the most likely site of specific interaction. 3. Formaldehyde has been used to test whether the central domains of histone H1 from calf thymus or from sea urchin sperm or histone H5 from chicken erythrocytes self-interact. 4. The cross-linking shown by each globular peptide was compared with that of its parent histone. 5. In all three cases the peptide cross-linked to a much lower extent than its intact parent histone and the observed cross-linked rates were roughly in proportion to the relative number of lysine residues parent histone and peptide. 6. It is concluded that there is no specific self-interaction between the globular domains of either H1 or H5 molecules in free solution. 7. This result suggests that specific H1/H1 protein/protein interactions are not the basic cause of chromatin condensation.

Animals↗
PubMed1990

Non-histone chromosomal protein HMG1 reduces the histone H5-induced changes in c.d. spectra of DNA: the acidic C-terminus of HMG1 is necessary for binding to H5.

Chemical cross-linking was used to study the interaction between non-histone high-mobility-group (HMG)1 and histone H5 in free solution. The presence of acidic C-terminal domain in HMG1 was shown to be a prerequisite for HMG1 binding to histone H5. The objective of this communication is to ascertain whether HMG1 could affect the conformation of DNA associated with a linker histone H5. Complexes of histone H5 with chicken erythrocyte DNA or an alternating purine-pyrimidine polynucleotide poly[d(A-T)] were prepared at different molar ratios H5/DNA. Changes in DNA conformation in the complexes with histone H5 or H5/HMG1 were monitored by circular dichroism (c.d.). Depending on the molar ratio H5/poly[d(A-T)], under conditions limiting the complex aggregation, three distinct types of c.d. spectra were observed. The addition of HMG1 to H5-DNA complexes reduced in all cases the histone H5-induced conformational changes in poly[d(A-T)]. The sensitivity of H5-poly[d(A-T)] complexes to HMG1 was inversely proportional to the amount of H5 in the complex. The effect of HMG1 was not observed upon removal of the acidic C-terminal domain of HMG1.

Animals↗
PubMed2004

Rapid replacement of somatic linker histones with the oocyte-specific linker histone H1foo in nuclear transfer.

The most distinctive feature of oocyte-specific linker histones is the specific timing of their expression during embryonic development. In Xenopus nuclear transfer, somatic linker histones in the donor nucleus are replaced with oocyte-specific linker histone B4, leading to the involvement of oocyte-specific linker histones in nuclear reprogramming. We recently have discovered a mouse oocyte-specific linker histone, named H1foo, and demonstrated its expression pattern in normal preimplantation embryos. The present study was undertaken to determine whether the replacement of somatic linker histones with H1foo occurs during the process of mouse nuclear transfer. H1foo was detected in the donor nucleus soon after transplantation. Thereafter, H1foo was restricted to the chromatin in up to two-cell stage embryos. After fusion of an oocyte with a cell expressing GFP (green fluorescent protein)-tagged somatic linker histone H1c, immediate release of H1c in the donor nucleus was observed. In addition, we used fluorescence recovery after photobleaching (FRAP), and found that H1foo is more mobile than H1c in living cells. The greater mobility of H1foo may contribute to its rapid replacement and decreased stability of the embryonic chromatin structure. These results suggest that rapid replacement of H1c with H1foo may play an important role in nuclear remodeling.

Animals↗
PubMed1978

Histone-histone interactions in a lower eukaryote, Tetrahymena thermophila.

The six pairwise interactions of Tetrahymena macronuclear histones H2A (formerly HX), H2B, H3, and H4 have been studied using the techniques of circular dichroism and continuous variation. Parallel experiments have been performed with calf thymus histones as controls, and the 12 possible interspecies pairs have also been examined. The behavior of three of the ciliate histones, H2A, H2B, and H3 is virtually identical with that of their vertebrate counterparts. Tetrahymena H4 exhibits a pattern of interactions identical with that of calf thymus H4, but displays significant quantitative differences in the strength of those interactions. Although we have not entirely eliminated the possibility that these differences may be artifactual, we suggest that they reflect the unique primary structure of Tetrahymena H4. These results extend the pattern of histone-histone interactions defined for plants, animals, and fungi to include the protists as well and imply the strong evolutionary conservatism of this pattern in spite of the electrophoretic and compositional differences which exist between homologous histones of different organisms. In addition, they demonstrate conclusively that histone HX should be redefined as Tetrahymena H2A.

Animals↗
PubMed1976

Primary structure and microheterogeneities of rat chloroleukemia histone H2A (histone ALK, IIbl or F2a2).

Rat chloroleukemia histone H2A, obtained from the F2a2 fraction, has been eluted in two peaks from a Biorex 70 column. The amino acid sequence of rat chloroleukemia histone H2A has been determined and compared to that of calf-thymus histone H2A. The structural studies performed on the tryptic peptides from the maleylated histone and on the thermolysin peptides from the native histone clearly demonstrate the existence of three molecular species of histone H2A depending on the nature of the amino acid residue at positions 16 and 99: H2A-alpha (Ser-16 and Lys-99) accounts for 60% and H2A-betaI (Thr-16 and Arg-99) and H2A-betaII (Ser-16 and Arg-99) for 20% each. A threonine residue at position 16 and a lysine residue at position 99 have been found in calf-thymus histone H2A.

Amino Acid Sequence↗
PubMed2006

Yeast Hsl7 (histone synthetic lethal 7) catalyses the in vitro formation of omega-N(G)-monomethylarginine in calf thymus histone H2A.

The HSL7 (histone synthetic lethal 7) gene in the yeast Saccharomyces cerevisiae encodes a protein with close sequence similarity to the mammalian PRMT5 protein, a member of the class of protein arginine methyltransferases that catalyses the formation of omega-N(G)-monomethylarginine and symmetric omega-N(G),N'(G)-dimethylarginine residues in a number of methyl-accepting species. A full-length HSL7 construct was expressed as a FLAG-tagged protein in Saccharomyces cerevisiae. We found that FLAG-tagged Hsl7 effectively catalyses the transfer of methyl groups from S-adenosyl-[methyl-3H]-L-methionine to calf thymus histone H2A. When the acid-hydrolysed radiolabelled protein products were separated by high-resolution cation-exchange chromatography, we were able to detect one tritiated species that co-migrated with an omega-N(G)-monomethylarginine standard. No radioactivity was observed that co-migrated with either the asymmetric or symmetric dimethylated derivatives. In control experiments, no methylation of histone H2A was found with two mutant constructs of Hsl7. Surprisingly, FLAG-Hsl7 does not appear to effectively catalyse the in vitro methylation of a GST (glutathione S-transferase)-GAR [glycine- and arginine-rich human fibrillarin-(1-148) peptide] fusion protein or bovine brain myelin basic protein, both good methyl-accepting substrates for the human homologue PRMT5. Additionally, FLAG-Hsl7 demonstrates no activity on purified calf thymus histones H1, H2B, H3 or H4. GST-Rmt1, the GST-fusion protein of the major yeast protein arginine methyltransferase, was also found to methylate calf thymus histone H2A. Although we detected Rmt1-dependent arginine methylation in vivo in purified yeast histones H2A, H2B, H3 and H4, we found no evidence for Hsl7-dependent methylation of endogenous yeast histones. The physiological substrates of the Hsl7 enzyme remain to be identified.

Amino Acid Sequence↗
PubMed1984

Cross-linking of histones with dimethyl 3,3'-dithiobispropionimidate. Interference by a one-end reaction modifying histones at lysine amino groups.

We have studied the HClO4-solubility of histones H1 and H5 in hen erythrocyte nuclei after treatment with the cross-linker dimethyl 3,3'-dithiobispropionimidate (DTPI). The amount of acid-soluble, non-cross-linked, H1 and H5 histones was drastically decreased, and that of acid-soluble H1/H5 histone dimers went through an optimum as the DTPI concentration was raised. Incubation of the HClO4-insoluble fraction with 2-mercaptoethanol regenerated the acid-solubility of H1/H5 histones in this fraction. When purified H1/H5 histones were treated with increasing concentrations of DTPI under non-cross-linking conditions, the amount of HClO4-soluble histones also greatly decreased, but to a much lesser extent if the DTPI treatment was followed by reduction with 2-mercaptoethanol. This decrease was inversely correlated to the proportion of amino groups modified. It is concluded that, when the cross-linker was used in large excess, the cross-linking reaction competed with a one-end reaction modifying the histones at lysine amino groups by cross-linker molecules, of which the imidoester groups that had not reacted were hydrolysed. It is suggested that this modification produced the changes in acid-solubility.

Animals↗