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PubMed2001

Physical association between the histone acetyl transferase CBP and a histone methyl transferase.

CBP (CREB-binding protein) is involved in transcriptional activation by a great variety of sequence-specific transcription factors. CBP has been shown to activate transcription through its histone acetyl transferase activity. Acetylation is a common post-translational modification of nucleosomal histone N-terminal tails, which generally correlates with transcriptional activation. Histone N-terminal tails are also modified by methylation but its functional consequences are largely unknown. Here we found that immunoprecipitation of CBP, or of the highly related p300, led to the co-immunoprecipitation of a robust histone methyl transferase (HMT) activity, indicating that CBP physically interacts with an HMT in living cells. The CBP-associated HMT is specific for lysines 4 and 9 of histone H3, which are known to be methylated in living cells. These results suggest that histone methylation could be involved in transcriptional activation. Furthermore, they raise the question of the link between histone methylation and acetylation.

Acetylation↗

PubMed2002

Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation.

Class II histone deacetylases (HDACs) 4, 5, 7, and 9 repress muscle differentiation through associations with the myocyte enhancer factor 2 (MEF2) transcription factor. MEF2-interacting transcription repressor (MITR) is an amino-terminal splice variant of HDAC9 that also potently inhibits MEF2 transcriptional activity despite lacking a catalytic domain. Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. Promyogenic signals provided by calcium/calmodulin-dependent kinase (CaMK) disrupt the interaction of MITR and HDACs with HP1. Since the histone methyl-lysine residues recognized by HP1 also serve as substrates for deacetylation by HDACs, the interaction of MITR and HDACs with HP1 provides an efficient mechanism for silencing MEF2 target genes by coupling histone deacetylation and methylation. Indeed, nucleosomal histones surrounding a MEF2-binding site in the myogenin gene promoter are highly methylated in undifferentiated myoblasts, when the gene is silent, and become acetylated during muscle differentiation, when the myogenin gene is expressed at high levels. The ability of MEF2 to recruit a histone methyltransferase to target gene promoters via HP1-MITR and HP1-HDAC interactions and of CaMK signaling to disrupt these interactions provides an efficient mechanism for signal-dependent regulation of the epigenetic events controlling muscle differentiation.

Animals↗

PubMed2003

An ERG (ets-related gene)-associated histone methyltransferase interacts with histone deacetylases 1/2 and transcription co-repressors mSin3A/B.

Covalent modifications of histone tails play important roles in gene transcription and silencing. We recently identified an ERG ( ets -related gene)-associated protein with a SET (suppressor of variegation, enhancer of zest and trithorax) domain (ESET) that was found to have the activity of a histone H3-specific methyltransferase. In the present study, we investigated the interaction of ESET with other chromatin remodelling factors. We show that ESET histone methyltransferase associates with histone deacetylase 1 (HDAC1) and HDAC2, and that ESET also interacts with the transcription co-repressors mSin3A and mSin3B. Deletion analysis of ESET reveals that an N-terminal region containing a tudor domain is responsible for interaction with mSin3A/B and association with HDAC1/2, and that truncation of ESET enhances its binding to mSin3. When bound to a promoter, ESET represses the transcription of a downstream luciferase reporter gene. This repression by ESET is independent of its histone methyltransferase activity, but correlates with its binding to the mSin3 co-repressors. In addition, the repression can be partially reversed by treatment with the HDAC inhibitor trichostatin A. Taken together, these data suggest that ESET histone methyltransferase can form a large, multi-protein complex(es) with mSin3A/B co-repressors and HDAC1/2 that participates in multiple pathways of transcriptional repression.

Animals↗

PubMed1999

Termination of human T cell tolerance to histones by presentation of histones and polyomavirus T antigen provided that T antigen is complexed with nucleosomes.

OBJECTIVE: To investigate whether polyomavirus T antigen linked to histones through nucleosome-T antigen complexes has the potential to terminate histone-specific T cell anergy. METHODS: Blood mononuclear cells from healthy individuals were used as the source to establish T cell lines initiated and maintained by T antigen, histones, nucleosome-T antigen complexes, or nucleosomes. Proliferative responses of these lines to T antigen, histones, and nucleosomes were determined. RESULTS: Whereas T cell lines could be established using T antigen or T antigen-nucleosome complexes, histones or nucleosomes did not have this potential. However, T cell lines selected by T antigen-nucleosome complexes responded subsequently to histones and nucleosomes. Identical results were obtained with murine and human nucleosomes, provided that they were complexed with T antigen. CONCLUSION: T antigen-specific T cells possess the potential to proliferate when interacting with an antigen-presenting cell that presents T antigen. In the presence of T antigens complexed with nucleosomes, T antigen-specific T cells offer bystander help that may terminate histone-specific T cell anergy. These T cells may progress into functional, autoimmune T cells if histones are properly presented.

Animals↗

PubMed1995

Chromosome condensation induced by fostriecin does not require p34cdc2 kinase activity and histone H1 hyperphosphorylation, but is associated with enhanced histone H2A and H3 phosphorylation.

Chromosome condensation at mitosis correlates with the activation of p34cdc2 kinase, the hyperphosphorylation of histone H1 and the phosphorylation of histone H3. Chromosome condensation can also be induced by treating interphase cells with the protein phosphatase 1 and 2A inhibitors okadaic acid and fostriecin. Mouse mammary tumour FT210 cells grow normally at 32 degrees C, but at 39 degrees C they lose p34cdc2 kinase activity and arrest in G2 because of a temperature-sensitive lesion in the cdc2 gene. The treatment of these G2-arrested FT210 cells with fostriecin or okadaic acid resulted in full chromosome condensation in the absence of p34cdc2 kinase activity or histone H1 hyperphosphorylation. However, phosphorylation of histones H2A and H3 was strongly stimulated, partly through inhibition of histone H2A and H3 phosphatases, and cyclins A and B were degraded. The cells were unable to complete mitosis and divide. In the presence of the protein kinase inhibitor starosporine, the addition of fostriecin did not induce histone phosphorylation and chromosome condensation. The results show that chromosome condensation can take place without either the histone H1 hyperphosphorylation or the p34cdc2 kinase activity normally associated with mitosis, although it requires a staurosporine-sensitive protein kinase activity. The results further suggest that protein phosphatases 1 and 2A may be important in regulating chromosome condensation by restricting the level of histone phosphorylation during interphase, thereby preventing premature chromosome condensation.

Alkaloids↗

PubMed1993

Interferon sensitivity of expression of histone H5/H1(0)-vaccinia thymidine kinase fusion genes expressed by recombinant vaccinia viruses is enhanced by shortening the histone sequence.

To elucidate the structural basis responsible for the reduced IFN sensitivity of expression of the histone H1(0) and H5 gene, integrated into the vaccinia virus genome, vaccinia virus thymidine kinase (VV-TK)-histone H1(0)/H5 fusion genes were constructed and translocated into the TK locus of the VV genome. The chimeric genes, consisting of parts of either of the two histone genes and the 5' or 3' half of the TK gene, respectively, were expressed as histone-TK fusion proteins under the control of either the VV-TK promoter or the early sequences of the VV 7.5K promoter. IFN sensitivity of the expression of histone-TK fusion genes was shown to be influenced by the relative length of the histone sequence. Expression of fusion genes containing more than 45% cellular sequence either from the 5' or the 3' part of one of the two histone genes showed clearly reduced IFN sensitivity compared to the expression of VV-TK. On the other hand, by further reducing the relative amount of histone H5 or H1(0) sequence to 32%, the IFN sensitivity of expression of the corresponding fusion gene was drastically enhanced to levels indistinguishable from those of VV-TK.

Animals↗

PubMed1993

Coordinate gene expression of five subclass histones and the putative transcription factors, HBP-1a and HBP-1b, of histone genes in wheat.

The expression of genes encoding five histones (H1, H2A, H2B, H3 and H4) and the putative transcription factors HBP-1a (17) and HBP-1b (c38) was examined during early germination and in various tissues of young wheat seedlings. The steady-state levels of core histone (H2A, H2B, H3 and H4) mRNAs were coordinately cell cycle-dependent and paralleled the rate of DNA synthesis during early germination, whereas the expression pattern of the linker histone (H1) genes differed. The five subclass histone genes were actively expressed in the meristematic tissues of young seedlings. Moreover, H1 genes were expressed in leaves that consist mostly of non-proliferating cells, in which core histone genes showed little expression. Quantitative alterations to the mRNAs of the putative transcription factors HBP-1a (17) and HBP-1b (c38) of wheat histone genes were similar to those of the core histone mRNAs, suggesting that both factors function in the cell cycle-dependent expression of wheat core histone genes.

Base Sequence↗

PubMed1988

Association of nucleosome core particle DNA with different histone oligomers. Transfer of histones between DNA-(H2A,H2B) and DNA-(H3,H4) complexes.

In non-denaturing low ionic strength gels, the titration of core DNA with H2A,H2B produces five well-defined bands. Quantitative densitometry and cross-linking experiments indicate that these bands are due to the successive binding of H2A,H2B dimers to core DNA. Only two bands are obtained with DNA-(H3,H4) samples. The slower of these bands is broad and presumably corresponds to two complexes containing one and two H3,H4 tetramers, respectively. In gels of higher ionic strength, DNA-(H2A,H2B) samples produce an ill-defined band, suggesting that the lifetime of the complexes containing H2A,H2B is relatively short. However, the low intensity of the free DNA band observed in these gels indicates that most of the DNA is associated with H2A,H2B. In agreement with this, our results obtained using different techniques (sedimentation, cross-linking, trypsin and nuclease digestions, and thermal denaturation) demonstrate that the association of H2A,H2B with core DNA occurs in free solution in both the absence and presence of NaCl (0.1 to 0.2 M). The low mobilities of DNA-(H2A,H2B) complexes, together with sedimentation and DNase I digestion results, indicate that the DNA in these complexes is not folded into the compact structure found in the core particle. Furthermore, non-denaturing gels have been used to study the dynamic properties of DNA-(H2A,H2B) and DNA-(H3,H4) complexes in 0.2 M-NaCl. Our results show that: (1) H2A,H2B and H3,H4 can associate, respectively, with DNA-(H3,H4) and DNA-(H2A,H2B) to produce complexes containing the four core histones; (2) DNA-(H2A,H2B) and DNA-(H3,H4) are able to transfer histones to free core DNA; (3) an exchange of histone pairs takes place between DNA-(H2A,H2B) and DNA-(H3,H4) and produces complexes with the same histone composition as that of the normal nucleosome core particle; and (4) although both histone pairs can exchange, histones H2A,H2B show a higher tendency than H3,H4 to migrate from one incomplete core particle to another. The complexes produced in these reactions have the same compact structure as reconstituted core particles containing the four core histones. Our kinetic results are consistent with a reaction mechanism in which the transfer of histones involves direct contacts between the reacting complexes. The possible participation of these spontaneous reactions on the mechanism of nucleosome assembly is discussed.

Animals↗

PubMed1976

Molecular analysis of the histone gene cluster of Psammechinus miliaris: III. Polarity and asymmetry of the histone-coding sequences.

Fragments of histone DNA produced by restriction endonucleases contain 5' and 3' termini with defined topologies relative to the histone-coding sequences. After limited resection with lambda-exonuclease, the 6 kb Hindlll histone DNA fragment (see Schaffner et al., 1976) hybridizes to H4 histone mRNA whether or not the DNA has been denatured. This shown that the coding sequence for the histone H4 is proximal to the 3' terminus of the Hindlll restriction fragment. By contrast, lambda-exonuclease digestion of the 6 kb EcoRI histone DNA fragment drastically reduces hybridization of the H4 mRNA. Hence in this molecule, the H4 DNA sequence is near a 5' terminus of the EcoRI restriction fragment. From these results and those described in the preceding paper (Schaffner et al., 1976), the polarity of the H4 gene is therefore 5' H2B leads to H4 leads to H1 3'. Cloned Psammechinus histone DNA (S. G. Clarkson, H. Smith, W. Schaffner, K. Gross, and M. Birnstiel, manuscript submitted for publication) may be strand-separated by electrophoresis. Highly purified histone mRNAs (Gross et al., 1976) all hybridize almost exclusively to the strand of lesser electrophoretic mobility. It follows that all coding sequences are arranged in tandem within the same DNA strand, and that hence they share the same polarity as the H4 DNA sequences. Transcription therefore proceeds in the gene cluster in the direction H4 leads to H2B leads to H3 leads to H2A leads to H1.

Animals↗

PubMed1987

The ubiquitinated histone species are enriched in histone H1-depleted chromatin regions.

Bovine thymus and trout testis chromatin were fractionated into regions which differed in their micrococcal nuclease accessibility and solubility properties, and the distribution of the ubiquitinated histone species among these chromatin regions was elucidated. Ubiquitinated (u) species of histones H2A and H2B were enriched in the nuclease-sensitive, low-ionic-strength, soluble fraction of both chromatins. These results indicate that the presence of ubiquitinated histones may alter nucleosome-nucleosome interactions and destabilize higher-order chromatin structures. Bovine thymus chromatin was separated into aggregation-resistant, salt-soluble and aggregation-prone, salt-insoluble chromatin fractions. The aggregation-resistant chromatin fraction depleted in H1 histones was enriched in uH2A and uH2B, with uH2B showing the greater enrichment. The chromatin fragments were also stripped and reconstituted with the H1 histones prior to fractionation. The results were the same as above: uH2A and uH2B were preferentially localized in the aggregation-resistant. H1-depleted chromatin fraction, suggesting that chromatin regions enriched in ubiquitinated histone species have a reduced affinity for the H1 histones. Thus, ubiquitinated histone species may be one of the contributing factors in the differential assembly of various parts of the genome.

Animals↗

PubMed1982

The site of histone H2b phosphorylated by a cyclic nucleotide independent histone kinase.

A cyclic nucleotide independent histone kinase was demonstrated in bovine thymus extract. This enzyme was very similar to that found previously in the cytoplasm and nucleus of human tonsillar lymphocytes (Faragó et al., 1973, Biochim. Biophys. Acta 297, 517 and 1974, ibid 370, 459). High-performance liquid chromatography of the tryptic phosphopeptides of calf thymus histones H1 and H2b phosphorylated by the histone kinase or by the catalytic subunit of cylic AMP dependent protein kinase showed that the intrinsic substrate specificity of these enzymes differed significantly. Under our experimental conditions the histone kinase phosphorylated preferentially the Ser-32 residue, and it did not phosphorylate the Ser-36 residue of histone H2b, while Ser-36 was phosphorylated preferentially by the cyclic AMP dependent protein kinase. A peptide containing the amino acid sequence of histone H2b from Gly-26 to Lys-34 (Gly-Lys-Lys-Arg-Lys-Arg-Ser-Arg-Lys-Ala) was synthesized. This peptide was a competitive inhibitor of histone H1 phosphorylation by the histone kinase and it was also a substrate for this enzyme.

Amino Acid Sequence↗

PubMed2003

Lymphocytes from bipolar and schizophrenic patients share common biochemical markers related to histone synthesis and histone cell membrane localization characteristic of an activated state.

In a previous communication, based on the total histone and histone variants' synthesis rates, biochemical parameters used for the characterization of the activation state of lymphocytes, we showed that a portion of the lymphocyte population obtained from peripheral blood of patients with bipolar disorder in the manic and/or depressed phases of the illness were in an activated state as opposed to normothymic patients and control subjects whose lymphocytes are in a resting, Go, state. In light of these previous findings, in the present investigation, we have analyzed total histone synthesis rates and the H2A and H3 histone variants' synthesis pattern of acid-extracted histones from the lymphocytes' nuclear fraction obtained from control subjects, patients with bipolar disorder in all phases of the illness, and patients with schizophrenia. Additional biochemical parameters, such as total cellular protein and DNA synthesis rates, were also studied. Moreover, recent findings from other investigators showed the association of histones on the plasma membrane fraction of PHA-activated, but not Go resting lymphocytes. Based on these results, acid-extracted proteins from the plasma membrane fraction obtained from control, bipolar patients in all phases of the illness, and schizophrenic patients were analyzed by immunoblotting using a polyclonal histone antibody, anti-H2B. All biochemical parameters tested show that a portion of the lymphocyte population from bipolar, i.e. manic and depressive, as well as schizophrenic patients are in an activated state and clearly indicate that the unusual for lymphocytes cell cycle-related histone biochemical properties are common to both disorders.

Adult↗

PubMed1997

Measurement of the frequency of histone displacement during the in vitro transcription of nucleosomes: RNA is a competitor for these histones.

Transcription through tandemly arranged nucleosomes was studied to determine the frequency at which the nucleosomes would disrupt and cause displacement of the associated histones to a competitor DNA. In order to more effectively preserve topological effects, the template that was used in the in vitro transcription system was a large covalently, closed circular plasmid (8.9 kb). The plasmid contained two promoters for T7 RNA polymerase, each separated by 4.4 kb, and transcription was done in the presence of topoisomerase I at physiological ionic strength. Nucleosome disruption was observed at an approximate frequency of 1 in 4 nucleosomes such that after several rounds of transcription on the plasmid 80% of the nucleosomes were disrupted. Unexpectedly, all four histones were found associated with the RNA rather than the competitor DNA. The histones bound the competitor DNA only after removal of the RNA by RNase A treatment. By analyzing the topological state of the competitor DNA, it was observed that the majority of the histones that were displaced from the RNA were able to re-form nucleosomes. Additional experiments were done to determine the reasons for the preferential binding of histones to the newly synthesized RNA. It was found that the large molecular weight RNA binds histones with an approximate 100-fold greater affinity relative to DNA when at physiological ionic strength. Within the cell, this high-affinity binding would be expected to require cellular mechanisms to regulate the interaction of RNA with histones. The relatively high frequency of displacement of all four histones during transcription is higher than what is observed in vivo and suggests that additional factors are needed to regulate this displacement. These observations are discussed and compared with previous studies that have examined the process of transcription through nucleosomes.

Animals↗

PubMed1985

Preparations of homeostatic thymus hormone consist predominantly of histones 2A and 2B and suggest additional histone functions.

The two major constituents in preparations of the homeostatic thymus hormone (HTH) were purified. Amino acid sequence analysis showed that the components (HTH alpha and HTH beta) are identical to histones H2A and H2B, suggesting the possibility that histones might have hitherto unrecognized occurrence and functions. If the HTH activities are not ascribed to the two histones in the preparation, they could only be derived from minor constituents present in minimal amounts. Therefore, the histone structures were scrutinized for properties of relevance in relation to hormone activities and for similarities with thymic hormones. Similarities between COOH-terminal regions of histones H2A, H2B, and H3 were noticed, as well as some similarities between NH2-terminal regions of histones and parts of recognized thymus hormones and related proteins. Potential signals, resembling cleavage sites in prohormones, are present in the histone structures, and further correlations with recently discovered ubiquitin functions may explain molecular mechanisms for actions of the HTH preparations. None of the observations is significant by itself, but the combined results suggest the hypothesis of different relationships and functions, including hormone-like activities, for some histones.

Amino Acid Sequence↗

PubMed2004

Histone H2A ubiquitination does not preclude histone H1 binding, but it facilitates its association with the nucleosome.

Histone H2A ubiquitination is a bulky posttranslational modification that occurs at the vicinity of the binding site for linker histones in the nucleosome. Therefore, we took several experimental approaches to investigate the role of ubiquitinated H2A (uH2A) in the binding of linker histones. Our results showed that uH2A was present in situ in histone H1-containing nucleosomes. Notably in vitro experiments using nucleosomes reconstituted onto 167-bp random sequence and 208-bp (5 S rRNA gene) DNA fragments showed that ubiquitination of H2A did not prevent binding of histone H1 but it rather enhanced the binding of this histone to the nucleosome. We also showed that ubiquitination of H2A did not affect the positioning of the histone octamer in the nucleosome in either the absence or the presence of linker histones.

Animals↗

PubMed2006

The histone chaperone Asf1 increases the rate of histone eviction at the yeast PHO5 and PHO8 promoters.

Eukaryotic gene expression starts off from a largely obstructive chromatin substrate that has to be rendered accessible by regulated mechanisms of chromatin remodeling. The yeast PHO5 promoter is a well known example for the contribution of positioned nucleosomes to gene repression and for extensive chromatin remodeling in the course of gene induction. Recently, the mechanism of this remodeling process was shown to lead to the disassembly of promoter nucleosomes and the eviction of the constituent histones in trans. This finding called for a histone acceptor in trans and thus made histone chaperones likely to be involved in this process. In this study we have shown that the histone chaperone Asf1 increases the rate of histone eviction at the PHO5 promoter. In the absence of Asf1 histone eviction is delayed, but the final outcome of the chromatin transition is not affected. The same is true for the coregulated PHO8 promoter where induction also leads to histone eviction and where the rate of histone loss is reduced in asf1 strains as well, although less severely. Importantly, the final extent of chromatin remodeling is not affected. We have also presented evidence that Asf1 and the SWI/SNF chromatin remodeling complex work in distinct parallel but functionally overlapping pathways, i.e. they both contribute toward the same outcome without being mutually strictly dependent.

Acid Phosphatase↗

PubMed1989

Antibodies specific to acetylated histones document the existence of deposition- and transcription-related histone acetylation in Tetrahymena.

In this study, we have constructed synthetic peptides which are identical to hyperacetylated amino termini of two Tetrahymena core histones (tetra-acetylated H4 and penta-acetylated hv1) and used them to generate polyclonal antibodies specific for acetylated forms (mono-, di-, tri-, etc.) of these histones. Neither of these antisera recognizes histone that is unacetylated. Immunoblotting analyses demonstrate that both transcription-related and deposition-related acetate groups on H4 are recognized by both antisera. In addition, the antiserum raised against penta-acetylated hv1 also recognizes acetylated forms of this variant. Immunofluorescent analyses with both antisera demonstrate that, as expected, histone acetylation is specific to macronuclei (or new macronuclei) at all stages of the life cycle except when micronuclei undergo periods of rapid replication and chromatin assembly. During this time micronuclear staining is also detected. Our results also suggest that transcription-related acetylation begins selectively in new macronuclei immediately after the second postzygotic division. Acetylated histone is not observed in new micronuclei during stages corresponding to anlagen development and, therefore, histone acetylation can be distributed asymmetrically in development. Equally striking is the rapid turnover of acetylated histone in parental macronuclei during the time of their inactivation and elimination from the cell. Taken together, these data lend strong support to the idea that modulation of histone acetylation plays an important role in gene activation and in chromatin assembly.

Acetylation↗

PubMed1973

Glutaraldehyde fixation of isolated eucaryotic nuclei. Evidence for histone-histone proximity.

Isolated chicken erythrocyte nuclei have been incubated with dilute concentrations of the bifunctional cross-linking agent glutaraldehyde (0-20 mM) in order to stabilize histone-histone interactions within the native nucleus. The kinetics of the disappearance of acid-soluble histones, free amino groups, and of individual histones have been observed to be pseudo first-order. Apparent first-order rate constants for the disappearance of individual histones correlate with the lysine mole percent of that fraction and follow the ranking, k(app): F1 > F2C > F2B >/= F2A2, F2A1, F3. Histone polymers were observed to form very rapidly during the fixation reaction. Partial fractionation and amino acid analyses of these polymers support the view that they are composed principally of cross-linked (F2C)(n) molecules (where n = 2 to approximately 8). The rate of glutaraldehyde reaction with free amino groups in histones is drastically reduced in solvents that promote chromatin decondensation (i.e., low ionic strengths in the absence of divalent cations) whereas the formation of cross-linked F2C polymers is less severely reduced. It is proposed that some F2C histones exist in close proximity within the isolated erythrocyte nucleus.

Amino Acids↗