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PubMed2006

The histone chaperone anti-silencing function 1 stimulates the acetylation of newly synthesized histone H3 in S-phase.

Anti-silencing function 1 (Asf1) is a highly conserved chaperone of histones H3/H4 that assembles or disassembles chromatin during transcription, replication, and repair. We have found that budding yeast lacking Asf1 has greatly reduced levels of histone H3 acetylated at lysine 9. Lysine 9 is acetylated on newly synthesized budding yeast histone H3 prior to its assembly onto newly replicated DNA. Accordingly, we found that the vast majority of H3 Lys-9 acetylation peaked in S-phase, and this S-phase peak of H3 lysine 9 acetylation was absent in yeast lacking Asf1. By contrast, deletion of ASF1 has no effect on the S-phase specific peak of H4 lysine 12 acetylation; another modification carried by newly synthesized histones prior to chromatin assembly. We show that Gcn5 is the histone acetyltransferase responsible for the S-phase-specific peak of H3 lysine 9 acetylation. Strikingly, overexpression of Asf1 leads to greatly increased levels of H3 on acetylation on lysine 56 and Gcn5-dependent acetylation on lysine 9. Analysis of a panel of Asf1 mutations that modulate the ability of Asf1 to bind to histones H3/H4 demonstrates that the histone binding activity of Asf1 is required for the acetylation of Lys-9 and Lys-56 on newly synthesized H3. These results demonstrate that Asf1 does not affect the stability of the newly synthesized histones per se, but instead histone binding by Asf1 promotes the efficient acetylation of specific residues of newly synthesized histone H3.

Acetylation↗
PubMed2006

Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription.

To gain insight into the molecular mechanism(s) whereby macrophages produce large amounts of IL-10, we analyzed IL-10 gene expression and temporally correlated it with modifications to chromatin associated with the IL-10 promoter. In resting cells, which make essentially no cytokines, the IL-10 promoter is associated with histones containing little or no detectable modifications. Macrophages stimulated in the presence of immune complexes begin to produce high levels of IL-10 pre-mRNA transcripts within minutes of stimulation. Coincident with this transcription was a rapid and dynamic phosphorylation of histone H3 at specific sites in the IL-10 promoter. Histone phosphorylation was closely followed by the binding of transcription factors to the IL-10 promoter. Blocking the activation of ERK prevented histone phosphorylation and transcription factor binding to the IL-10 promoter. In contrast to histone phosphorylation, the peak of histone acetylation at this promoter did not occur until after transcription had peaked. Inhibition of histone deactylase did not alter IL-10 gene expression, suggesting that phosphorylation but not acetylation was the proximal event responsible for IL-10 transcription. Our findings reveal a rapid and well-orchestrated series of events in which ERK activation causes a rapid and transient phosphorylation of histone H3 at specific regions of the IL-10 promoter, resulting in a transient exposure of the IL-10 promoter to the transcription factors that bind there. This exposure is essential for the efficient induction of IL-10 gene expression in macrophages. To our knowledge, this represents a unique way in which the expression of a cytokine gene is regulated in macrophages.

Acetylation↗
PubMed2001

DNA repair: spot(light)s on chromatin.

Chromatin modifications regulate many nuclear processes. Recent studies on the phosphorylation of a histone 2A variant have revealed that this chromatin modification is a general and evolutionarily conserved cellular response to DNA double-strand breaks.

Animals↗
PubMed2003

Correlation between butyrate-induced histone hyperacetylation turn-over and c-myc expression.

Transcriptionally active chromatin has an high level of histone acetylation, a post-transcriptional modification known to alter nucleosomal conformation increasing the accessibility of transcription factors to DNA. Recent studies have led new interest in histone acetylase and deacetylase because of their role as transcription factors. Sodium butyrate, a known reversible inhibitor of histone deacetylase, modulates a large number of genes. This report is focused on the modulation of the c-myc oncogene expression by butyrate. In HeLa cells, treated with butyrate and then exposed to butyrate-free medium, we established a correlation between the reactivation kinetic of c-myc expression and the increase in level of histone H4 acetylation. Both parameters, in cells exposed to butyrate-free medium, after showing a rebound effect, return to the control level. This trend was confirmed by quantitative analysis of the level of histone acetylation and of c-myc expression in the three distinct class of nucleosomal fragments with different transcriptional activity. In this chase process, we also detected a concomitant enrichment in c-myc sequences in the "active" chromatin fractions and decreased presence in the inactive nucleosomal fragment. Therefore we here demonstrate an excellent correlation between histone hyperacetylation and reactivation of a specific gene (c-myc).

Acetylation↗
PubMed1991

Arginine residues involved in strong histone--DNA interactions to fold DNA into the nucleosome core particle.

The numbers of the arginine residues involved in strong histone-DNA interactions to fold DNA into a nucleosome core particle were determined for each of the four core histones, by kinetic studies of chemical modification of the residues in the nucleosome core particle. It was suggested that the arginines in the globular region of H3 histone make major contributions to the strong binding of the octameric histones to the core DNA.

Animals↗
PubMed2003

Replication of the chicken beta-globin locus: early-firing origins at the 5' HS4 insulator and the rho- and betaA-globin genes show opposite epigenetic modifications.

Chromatin structure is believed to exert a strong effect on replication origin function. We have studied the replication of the chicken beta-globin locus, whose chromatin structure has been extensively characterized. This locus is delimited by hypersensitive sites (HSs) that mark the position of insulator elements. A stretch of condensed chromatin and another HS separate the beta-globin domain from an adjacent folate receptor (FR) gene. We demonstrate here that in erythroid cells that express the FR but not the globin genes, replication initiates at four sites within the beta-globin domain, one at the 5' HS4 insulator and the other three near the rho- and beta(A)-globin genes. Three origins consist of G+C-rich sequences enriched in CpG dinucleotides. The fourth origin is A+T rich. Together with previous work, these data reveal that the insulator origin has unmethylated CpGs, hyperacetylated histones H3 and H4, and lysine 4-methylated histone H3. In contrast, opposite modifications are observed at the other G+C-rich origins. We also show that the whole region, including the stretch of condensed chromatin, replicates early in S phase in these cells. Therefore, different early-firing origins within the same locus may have opposite patterns of epigenetic modifications. The role of insulator elements in DNA replication is discussed.

Animals↗
PubMed1995

Effect of buffer composition on the migration order and separation of histone H1 subtypes.

The effects of different buffer concentrations and compositions on the elution order and separation of H1 histone subtypes and their phosphorylated modifications isolated from several species was studied using high-performance capillary electrophoresis (CE). Various cations and anions were tested in an untreated silica capillary and low pH buffers, in the presence of the dynamic coating agent hydroxypropylmethyl cellulose. It was found that the cations and anions of buffers have a remarkable influence on both the efficiency and the selectivity of protein separations. A triethylammonium methanephosphonate system proved efficacious for the separation of rat histone subtype H1c from H1e and a perchlorate/triethylammonium phosphate system for the analysis of chicken and mouse linker histones. CE provides an attractive alternative to high-performance liquid chromatography and conventional gel electrophoresis.

Animals↗
PubMed2005

Histone structure and nucleosome stability.

Histone proteins play essential structural and functional roles in the transition between active and inactive chromatin states. Although histones have a high degree of conservation due to constraints to maintain the overall structure of the nucleosomal octameric core, variants have evolved to assume diverse roles in gene regulation and epigenetic silencing. Histone variants, post-translational modifications and interactions with chromatin remodeling complexes influence DNA replication, transcription, repair and recombination. The authors review recent findings on the structure of chromatin that confirm previous interparticle interactions observed in crystal structures.

Animals↗
PubMed2006

The Heterochromatin Protein 1 family.

Heterochromatin Protein 1 (HP1) was first discovered in Drosophila as a dominant suppressor of position-effect variegation and a major component of heterochromatin. The HP1 family is evolutionarily conserved, with members in fungi, plants and animals but not prokaryotes, and there are multiple members within the same species. The amino-terminal chromodomain binds methylated lysine 9 of histone H3, causing transcriptional repression. The highly conserved carboxy-terminal chromoshadow domain enables dimerization and also serves as a docking site for proteins involved in a wide variety of nuclear functions, from transcription to nuclear architecture. In addition to heterochromatin packaging, it is becoming increasingly clear that HP1 proteins have diverse roles in the nucleus, including the regulation of euchromatic genes. HP1 proteins are amenable to posttranslational modifications that probably regulate these distinct functions, thereby creating a subcode within the context of the 'histone code' of histone posttranslational modifications.

Animals↗
PubMed2006

Mass spectrometric characterization of human histone H3: a bird's eye view.

The modification of H3 in asynchronous HeLa cells was profiled using Top Down Mass Spectrometry. A broad distribution of species differing by 14 Da and containing less than 3% unmodified protein was observed for all three variants. Species of up to +168 Da were observed for H3.1, and fragmentation of all species by Electron Capture Dissociation (ECD) revealed approximately 5% methylation of K4 and approximately 50% dimethylation of K9. K14 and K23 were major sites of acetylation. H3.3 was slightly hypermodified with the apex of the distribution shifted by approximately +14 Da compared to H3.1. H3.1 (50% and 15%) from colchicine-treated cells was monophosphorylated and diphosphorylated, respectively, with equivalent modification of S10 and S28.

Acetylation↗
PubMed2005

Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes.

The treatment of cancer through the development of new therapies is one of the most important challenges of our time. The decoding of the human genome has yielded important insights into the molecular basis of physical disorders, and in most cases a connection between failures in specific genes and the resulting clinical symptoms can be made. The modulation of epigenetic mechanisms enables, by definition, the alteration of cellular phenotype without altering the genotype. The information content of a single gene can be crucial or harmful, but the prerequisite for a cellular effect is active gene transcription. To this end, epigenetic mechanisms play a very important role, and the transcription of a given gene is directly influenced by the modification pattern of the surrounding histone proteins as well as the methylation pattern of the DNA. These processes are effected by different enzymes which can be directly influenced through the development of specific modulators. Of course, all genetic information is written as a four-character code in DNA. However, epigenetics describes the art of reading between the lines.

Acetylation↗
PubMed2001

Dynamic chromatin remodeling on the HER2 promoter in human breast cancer cells.

Deregulation of the HER2 oncogene occurs in 30% of human breast cancers and correlates with poor prognosis and increased propensity for metastasis. Since the molecular basis of HER2 overexpression in human cancers is not known, we sought to determine whether chromatin remodeling pathways are involved in the regulation of HER2 expression. We report that compared with breast cancer cells expressing a low level of HER2, HER2-overexpressing breast cancer cells contained significantly higher levels of acetylated and phosphorylated histone H3, and acetylated histone H4 associated with the HER2 promoter. Decreased recruitment of histone deacetylases in the promoter is also noted in the HER2-overexpressing cell. The association of acetylated histone H4 with HER2 gene chromatin and HER2 expression in breast cancer cells was upregulated by an inhibitor of histone deacetylases. Treatment with histone deacetylase inhibitor also reduced the association of histone deacetylase-1 and -2 with the HER2 promoter. In addition, the tumor promoters 12-O-tetradecanoylphorbol-13-acetate and okadaic acid stimulated the association of phosphorylated histone H3 on serine 10 with the HER2 promoter and also stimulated HER2 expression. These findings identify histone acetylation and histone phosphorylation as novel regulatory modifications that target HER2 gene chromatin, and suggest that elevated levels of these chromatin-relaxing components in the vicinity of the HER2 gene promoter may constitute an important non-genomic mechanism of HER2 overexpression in human breast cancer.

Acetylation↗
PubMedDate not supplied

Structural aspects of histone complexes and nucleosomes revealed by the accessibility of cysteine side chains.

Chemical modification with 5,5'-dithiobis-(2-nitrobenzoic acid) shows that histone H3 cysteines 110 (chicken) or 96 and 110 (calf) are completely protected in native chromatin and core particles but become unmasked simultaneously during a salt induced dissociation. In whole histone extracted from chicken erythrocyte chromatin, H3 Cys-110 residues experience a uniform environment at 2 M NaCl and pH 5.5. In whole histone extracted under the same conditions from calf thymus, H3 Cys-96 provides a more accessible thiol group than Cys-110. At higher pH values a conformational heterogeneity is induced causing a partial exposure of both cysteine side chains. The kinetic approach described in the present work provides a highly sensitive means to probe the homogeneity of H3 containing protein complexes.

Animals↗
PubMed2004

B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5.

Immunoglobulin heavy chain rearrangement (V(H)-to-DJ(H)) occurs only in B cells, suggesting it is inhibited in other lineages. Here we found that in the mouse V(H) locus, methylation of lysine 9 on histone H3 (H3-K9), a mark of inactive chromatin, was present in non-B lineage cells but was absent in B cells. As others have shown that H3-K9 methylation can inhibit V(D)J recombination on engineered substrates, our data support the idea that H3-K9 methylation inhibits endogenous V(H)-to-DJ(H) recombination. We also show that Pax5, a transcription factor required for B cell commitment, is necessary and sufficient for the removal of H3-K9 methylation in the V(H) locus and provide evidence that one function of Pax5 is to remove this inhibitory modification by a mechanism of histone exchange, thus allowing B cell-specific V(H)-to-DJ(H) recombination.

Animals↗
PubMed2002

Differential patterns of histone methylation and acetylation distinguish active and repressed alleles at X-linked genes.

In female mammals, one of the two X chromosomes is inactivated to compensate for the difference in dosage of X-linked genes between males and females. X inactivation involves sequential alterations to the chromatin that ultimately lead to the transcriptional repression of genes on the X chromosome. Here, histone methylation and acetylation along X-linked genes are investigated by chromatin immunoprecipitation (ChIP) of adult fibroblast cell lines. At PGK1 and HPRT, chromatin on the active X chromosome reveals H3 lysine 4 methylation and acetylation of histones H3 and H4. These modifications are absent on the repressed allele, which is marked by H3 lysine 9 methylation. On the expressed allele of XIST (on the inactive X chromosome), we found that H3 acetylation is confined to the promoter, whereas H3 lysine 4 methylation and H4 acetylation are present along the entire gene. On the repressed XIST allele, in contrast, the promoter and gene exhibit H3 lysine 9 methylation. At only 1.5 kb upstream of the XIST gene, chromatin on the inactive X chromosome has strongly reduced levels of H4 acetylation and is marked by both H3 lysine 9 and H3 lysine 4 methylation. These data demonstrate that patterns of histone methylation and acetylation are distinct along and upstream of XIST and suggest that the inactive X chromatin configuration occurs at a region close to the 5' end of the gene.

Acetylation↗
PubMed1980

Calcium-dependent phosphorylation of histone H3 in butyrate-treated HeLa cells.

Ca2+ is prominant in the control of cell proliferation and function. However, the biochemical mechanism(s) mediating its effects on nuclear events is unknown. We report here that Ca2+, at physiological concentrations, stimulates the phosphorylation of histone H3 by an endogenous protein kinase in HeLa cell nuclei. Also, pretreatment of cells with Na butyrate, which increases histone acetylation, selectively increases the susceptability of histone H3 to phosphorylation by the protein kinase. Our results reveal a potential link between histone H3 acetylation and phosphorylation, modifications which are thought to have important effects on chromatin structure and function and suggest a possible mechanism whereby stimuli at the cell surface (such as hormones, mitogens and drugs) may influence biochemical events at the nuclear level; changes in the intracellular Ca2+ concentration may influence the phosphorylation of chromosomal proteins, mediated by Ca2+ -dependent kinases in th nucleus.

Acetylation↗
PubMed2006

Leishmania histone H1 overexpression delays parasite cell-cycle progression, parasite differentiation and reduces Leishmania infectivity in vivo.

Episomal expression of Leishmania histone H1 sense mRNAs in Leishmania major promastigotes was found previously to result in overexpression of this molecule and to reduce parasite infectivity in vitro. Herein, we evaluated the in vivo infectivity of these transfectants, in BALB/c mice, and showed that it is dramatically reduced. No lesions were observed in this group of mice and this was associated with an extremely low number of parasites both in the footpad and in the draining lymph nodes. Interestingly, the transfectants-reduced infectivity was associated with a delay in their cell-cycle progression and differentiation to axenic amastigotes, assessed in vitro. Therefore, the dramatic reduction in their infectivity may be attributed to the above-mentioned phenotypic modifications. As the metazoan linker histone H1(0) homologue is known to delay cell-cycle progression in mammalian cells we investigated whether its Leishmania counterpart, which possesses homology to its C-terminal region, when expressed in mammalian cells may also affect their cell-cycle progression. It was thus shown that Leishmania histone H1 expressed in COS7 and NIH 3T3 cells, delays cell-cycle progression in these cells too. The latter strengthens the phenotype observed in Leishmania and provides evidence that critical functions of histone H1 molecules are conserved throughout evolution.

Animals↗
PubMed1989

Modifications in molecular mechanisms associated with control of cell cycle regulated human histone gene expression during differentiation.

Histone proteins are preferentially synthesized during the S-phase of the cell cycle, and the temporal and functional coupling of histone gene expression with DNA replication is mediated at both the transcriptional and posttranscriptional levels. The genes are transcribed throughout the cell cycle, and a 3-5-fold enhancement in the rate of transcription occurs during the first 2 h following initiation of DNA synthesis. Control of histone mRNA stability also accounts for some of the 20-100fold increase in cellular histone mRNA levels during S-phase and for the rapid and selective degradation of the mRNAs at the natural completion of DNA replication or when DNA synthesis is inhibited. Two segments of the proximal promoter, designated Sites I and II, influence the specificity and rate of histone gene transcription. Occupancy of Sites I and II during all periods of the cell cycle by three transacting factors (HiNF-A, HiNF-C, and HiNF-D) suggests that these protein-DNA interactions are responsible for the constitutive transcription of histone genes. Binding of HiNF-D in Site II is selectively lost, whereas occupancy of Site I by HiNF-A and -C persists when histone gene transcription is down regulated when cells terminally differentiate. These results are consistent with a primary role for interactions of HiNF-D with a proximal promoter element in rendering cell growth regulated human histone genes transcribable in proliferating cells.

Amino Acid Sequence↗