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PubMed2006

Control of cardiac growth by histone acetylation/deacetylation.

Histones control gene expression by modulating the structure of chromatin and the accessibility of regulatory DNA sequences to transcriptional activators and repressors. Posttranslational modifications of histones have been proposed to establish a "code" that determines patterns of cellular gene expression. Acetylation of histones by histone acetyltransferases stimulates gene expression by relaxing chromatin structure, allowing access of transcription factors to DNA, whereas deacetylation of histones by histone deacetylases promotes chromatin condensation and transcriptional repression. Recent studies demonstrate histone acetylation/deacetylation to be a nodal point for the control of cardiac growth and gene expression in response to acute and chronic stress stimuli. These findings suggest novel strategies for "transcriptional therapies" to control cardiac gene expression and function. Manipulation of histone modifying enzymes and the signaling pathways that impinge on them in the settings of pathological cardiac growth, remodeling, and heart failure represents an auspicious therapeutic approach.

Acetylation↗
PubMed2004

High-resolution genome-wide mapping of histone modifications.

The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules. Post-translational histone modifications play an essential role in modifying chromatin structure. Here we apply a combination of SAGE and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5' end of a gene's coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5' end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes.

Chromatin↗
PubMed2005

Histone H3 acetylation is associated with reduced p21(WAF1/CIP1) expression by gastric carcinoma.

Histone acetylation appears to play an important role in transcriptional regulation. Inactivation of chromatin by histone deacetylation is involved in the transcriptional repression of several tumour suppressor genes, including p21(WAF1/CIP1). However, the in vivo status of histone acetylation in human cancers, including gastric carcinoma, is not well understood. This study shows that histone H3 in the p21(WAF1/CIP1) promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p21(WAF1/CIP1) expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p21(WAF1/CIP1) promoter and coding regions in 10 (34.5%) and 10 (34.5%) of 29 gastric carcinoma specimens, respectively. Hypoacetylation of histone H4 in the p21(WAF1/CIP1) promoter and coding regions was observed in 6 (20.7%) and 16 (55.2%) of 29 gastric carcinoma specimens, respectively. p21(WAF1/CIP1) mRNA levels were associated with histone H3 acetylation status in the p21(WAF1/CIP1) promoter region (p = 0.047) but not p53 mutation status (p = 0.460). In gastric carcinoma cell lines, expression of p21(WAF1/CIP1) protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p21(WAF1/CIP1) promoter region. Hyperacetylation of histone H4 in the p21(WAF1/CIP1) promoter region did not appear to be associated with increased expression. Induction of p21(WAF1/CIP1) protein expression was associated with hyperacetylation of histones H3 and H4 in the p21(WAF1/CIP1) coding region. Expression of a dominant-negative mutant of p53 reduced expression of p21(WAF1/CIP1) protein. Histone H4 acetylation in both the promoter and coding regions of the p21(WAF1/CIP1) gene in cells expressing dominant-negative p53 was less than half of that in cells expressing wild-type p53, whereas histone H3 acetylation in both the promoter and coding regions was slightly reduced (by approximately 20%) in cells expressing the dominant-negative p53. These findings provide evidence that alteration of histone acetylation occurs in human cancer tissue specimens such as those from gastric carcinoma.

Acetylation↗
PubMed2007

Histone H4 N-terminal acetylation in Kasumi-1 cells treated with depsipeptide determined by acetic acid-urea polyacrylamide gel electrophoresis, amino acid coded mass tagging, and mass spectrometry.

Disrupted patterns of acetylation and deacetylation of core histones play an important role in silencing transcription of hematopoietic important genes in acute myeloid leukemia (AML). A thorough investigation of these mechanisms and the response to pharmacologic modifiers will provide a better understanding of the role of histone acetylation in leukemogenesis. We describe here an analytical approach that combines acid urea polyacrylamide gel electrophoresis (AU-PAGE), amino acid coded mass tagging (AACM), and mass spectrometry (MS) for the investigation of histone acetylation patterns. The combined approach was used to follow the dynamics of H4 acetylation in Kasumi-1 cells harboring the fusion gene AML1/ETO shown to aberrantly recruit histone deacetylases (HDACs). The histones in Kasumi-1 cells were labeled by growing the cells in media in which lysine was replaced with stable isotope-labeled lysine (Lys-D4). Labeled and unlabeled cells were treated with depsipeptide and analyzed at different time points (0, 4, 8, 12, 24, and 48 h). The cells were mixed, the histone was extracted, and acetylated H4 isoforms were separated using AU-PAGE before in-gel trypsin digestion. The digests were analyzed by MALDI-TOF MS. Peptides were identified by mass and isotope pattern. LC-MS/MS of Arg-C digests were also performed to verify the acetylation pattern for H4. The major pattern of acetylation was determined as follows: initial acetylation at K16, followed by acetylation at K12, and finally acetylation of either K8 and/or K5.

Acetic Acid↗
PubMed1986

Transcription unit of the chicken histone H5 gene and mapping of H5 pre-mRNA sequences.

We have analyzed the transcription unit of the gene coding for the erythrocyte-specific histone H5. RNA transcripts elongated in vitro by permeabilized immature cells hybridized to the template strand of the structural gene as well as to 3'-flanking sequences. Approximately 90% of the engaged RNA polymerase II molecules terminate transcription within a region of about 500 base pairs immediately downstream of the polyadenylation site. S1 nuclease protection experiments indicated that the downstream sequences are also transcribed in vivo, their relative amounts reflecting the distribution of RNA polymerases observed in vitro. RNA molecules extending up to 1.14 kilobase pairs downstream of the polyadenylation site were detected, but no unique site of termination was found. The sequence of the transcription termination region shows no obvious homology to those of other RNA polymerase II termination regions. The possible involvement of altered DNA and/or chromatin structures in the transcription termination process is discussed.

Animals↗
PubMed1991

Multiple control level governing H10 mRNA and protein accumulation.

We have studied the variation of histone H10 and of its coding mRNA during rat liver regeneration after partial hepatectomy. Our data showed that while H10 decreased when cell proliferation was initiated, H10 mRNA accumulated in a proliferation-dependent manner as did H3 mRNA. These results showed two interesting aspects of the regulation of H10 expression in vivo, confirming results we have obtained previously in vitro: first H10 mRNA accumulation is a proliferation-dependent event; second, H10 protein accumulation may be uncoupled from that of its coding mRNA.

Animals↗
PubMedDate not supplied

Cytoskeletal neurofilament gene expression in brain tissue from Alzheimer's disease patients. I. Decrease in NF-L and NF-M message.

The cytoskeletal changes seen in brains of patients with Alzheimer's disease include neurofibrillary tangles, neuritic plaques, Hirano bodies, and granulovacuolar degeneration. Northern and slot blot analyses were used to investigate the expression of the genes coding for actin, tubulin, neurofilaments, and histone in brain tissue from Alzheimer's disease patients and normal aged controls. We found a marked decrease of 94% in the expression of the neurofilament gene coding for the medium size subunit (150 kDa) and a 73% decrease in the expression of the gene coding for the small subunit (68 kDa) in Alzheimer's disease patients as compared to controls. Expression of the other genes, such as actin and histone, did not show any significant difference. Expression of the gene coding for medium size, neurofilament gene was not decreased in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease. This abnormality in neurofilament gene expression may explain some of the pathologic features found in Alzheimer's disease patients.

Aged↗
PubMed1986

Involvement of the 5'-leader sequence in coupling the stability of a human H3 histone mRNA with DNA replication.

Two lines of evidence derived from fusion gene constructs indicate that sequences residing in the 5'-nontranslated region of a cell cycle-dependent human H3 histone mRNA are involved in the selective destabilization that occurs when DNA synthesis is terminated. The experimental approach was to construct chimeric genes in which fragments of the mRNA coding regions of the H3 histone gene were fused with fragments of genes not expressed in a cell cycle-dependent manner. After transfection in HeLa S3 cells with the recombinant plasmids, levels of fusion mRNAs were determined by S1 nuclease analysis prior to and following DNA synthesis inhibition. When the first 20 nucleotides of an H3 histone mRNA leader were replaced with 89 nucleotides of the leader from a Drosophila heat-shock (hsp70) mRNA, the fusion transcript remained stable during inhibition of DNA synthesis, in contrast to the rapid destabilization of the endogenous histone mRNA in these cells. In a reciprocal experiment, a histone-globin fusion gene was constructed that produced a transcript with the initial 20 nucleotides of the H3 histone mRNA substituted for the human beta-globin mRNA leader. In HeLa cells treated with inhibitors of DNA synthesis and/or protein synthesis, cellular levels of this histone-globin fusion mRNA appeared to be regulated in a manner similar to endogenous histone mRNA levels. These results suggest that the first 20 nucleotides of the leader are sufficient to couple histone mRNA stability with DNA replication.

Animals↗
PubMed1994

Histone H1 expressed in Saccharomyces cerevisiae binds to chromatin and affects survival, growth, transcription, and plasmid stability but does not change nucleosomal spacing.

Histone H1 is proposed to serve a structural role in nucleosomes and chromatin fibers, to affect the spacing of nucleosomes, and to act as a general repressor of transcription. To test these hypotheses, a gene coding for a sea urchin histone H1 was expressed from the inducible GAL1 promoter in Saccharomyces cerevisiae by use of a YEp vector for high expression levels (strain YCL7) and a centromere vector for low expression levels (strain YCL1). The H1 protein was identified by its inducibility in galactose, its apparent molecular weight, and its solubility in 5% perchloric acid. When YCL7 was shifted from glucose to galactose for more than 40 h to achieve maximal levels of H1, H1 could be copurified in approximately stoichiometric amounts with core histones of Nonidet P-40-washed nuclei and with soluble chromatin fractionated on sucrose gradients. While S. cerevisiae tolerated the expression of low levels of H1 in YCL1 without an obvious phenotype, the expression of high levels of H1 correlated with greatly reduced survival, inhibition of growth, and increased plasmid loss but no obvious change in the nucleosomal repeat length. After an initial induction, RNA levels for GAL1 and H1 were drastically reduced, suggesting that H1 acts by the repression of galactose-induced genes. Similar effects, but to a lower extent, were observed when the C-terminal tail of H1 was expressed.

Animals↗
PubMed1994

The Leishmania infantum histone H3 possesses an extremely divergent N-terminal domain.

The isolation of a Leishmania cDNA clone coding for an antigen identified as the histone H3 is described. The nucleotide sequence of the cDNA predicts that the Leishmania histone H3 contains 129 residues and that it has a molecular mass of 14,620 Da. Comparison of the amino acid sequence with the consensus sequence of the eukaryotic histone H3 shows that the Leishmania protein has a highly conserved globular region and an extremely divergent amino-terminal portion.

Amino Acid Sequence↗
PubMed1995

The human replacement histone H3.3B gene (H3F3B).

H3.3 is a replacement histone subtype that is encoded by two replication-independent genes termed H3.3A and H3.3B, respectively. We have isolated a fullsize H3.3 cDNA clone from an oligo(dT)-primed human testicular cDNA library. Subsequently, the corresponding gene was isolated from a human cosmid library and was identified as the H3.3B gene. It was the only histone gene on this 42-kb cosmid clone. The gene structure shows characteristic features of an H3.3 gene. First, it contains an intron of about 0.5 kb in the 5' untranslated region and two smaller introns within the coding gene portion. Second, no histone gene-specific dyad symmetry element was found in the 3' untranslated region, but three putative polyadenylation signals were detected downstream of the gene. The corresponding transcripts were detected by Northern blot analysis using poly(A)+ RNA from testis and from the HEK293 tumor cell line. The newly discovered human H3.3B gene (HGMW-approved symbol H3F3B) was mapped by fluorescence in situ hybridization to the telomeric region of chromosome 17 (17q25). This localization of the H3.3B gene and its solitary arrangement contrast with the majority of the replication-dependent histone genes, which form a large cluster on chromosome 6 and a second cluster on chromosome 1.

Amino Acid Sequence↗
PubMed1997

H3.3A variant histone mRNA containing an alpha-globin insertion: modulated expression during mouse gametogenesis correlates with meiotic onset.

Replacement-variant H3.3 histones have been isolated and sequenced in different eukaryotes, but no functional H3.3A gene has been characterized in the mouse so far. We have cloned an H3.3A cDNA from a mouse fetal ovary library, differentially screened with testis versus somatic cDNA probes. We showed this gene contains a region homologous to the reverse and complementary alpha-globin gene. We believe such a structure could have been generated by retroposition during the evolution of both globin and histone gene families. The sequence coding for H3.3A is 76.6% homologous to the mouse H3.3B gene at the nucleotide level and differs in only one amino acid at the protein level. The high degree of homology between these genes and the H3.3 variant histones from other eukaryotes reveals the conservation of these replication-independent class of histones throughout evolution. Analysis of gene expression reveals a developmental regulation concurrent with meiotic progression, with the highest level of transcript detection coincident with meiotic onset during both oogenesis and spermatogenesis.

Amino Acid Sequence↗
PubMed1985

Replacement variant histone genes contain intervening sequences.

The nucleotide sequences of two chicken histone genes encoding replacement variant H3.3 polypeptides are described. Unlike the replication variant genes of chickens (and almost all other organisms), these genes contain intervening sequences; introns are present in both genes in the 5' noncoding and coding sequences. Furthermore, the replacement variant histone mRNAs are post-transcriptionally polyadenylated. The locations, but not the sizes, of the two introns within the coding segments of the two genes have been exactly conserved, whereas the intron positions in their respective 5' flanking regions differ. Although both H3.3 genes predict the identical histone polypeptide sequence, they are as different from one another as each of them is from a more common replication variant H3.2 gene in silent base substitutions within the coding sequences. Thus, the H3.3 polypeptide sequence has been precisely maintained over a great evolutionary period, suggesting that this class of histones performs a strongly selected biological function. Although replacement variant histones can account for more than 50% of the total H3 protein in the nuclei of specific chicken tissues, the steady-state level of H3.3 mRNA is nearly the same (and is quite low) in all tissues and ages of animals examined. These properties suggest novel mechanisms for the control of the basal histone biosynthesis which takes place outside of the S phase of the cell cycle.

Age Factors↗
PubMed1977

Application of the avidin-biotin method of gene enrichment to the isolation of long double-stranded DNA containing specific gene sequences.

A method of enriching for long double-stranded segments of eukaryotic DNA carrying particular genes is described. A purified RNA coded for by the gene is covalently attached to biotin via the protein, cytochrome c. This modified RNA is hybridized to total nuclear, double-stranded DNA under conditions that allow the formation of R-loops. Avidin, which has a high affinity for biotin, is covalently attached to polymer spheres. The complexes of avidin-spheres with DNA:RNA-biotin R-loop hybrids band in CsCl at a much lower bouyant density than does free DNA. This density is a function of the length of DNA coupled per avidin-sphere. This method was used to prepare very long double-strands of DNA highly enriched in the coding sequences for the large rRNAs of D. melanogaster and L. donovani and the histone mRNAs of S. purpuratus.

Animals↗
PubMed1980

Leader sequences of Strongylocentrotus purpuratus histone mRNAs start at a unique heptanucleotide common to all five histone genes.

We have determined the sequence of the untranslated leader nucleotides of all five histone mRNAs from Strongylocentrotus purpuratus by the dideoxy chain termination method. Total polysomal RNA from sea urchin embryos was used as a substrate for cDNA synthesis primed by specific DNA restriction fragments. Each of the primers was derived from the 5'-terminal part of the coding region for a different histone protein. The five histone mRNA leader sequences are different in length and primary structure. The 5' termini of all five histone mRNAs coincide with the unique heptanucleotide Py-Py-A-T-T-C-Pu in genomic DNA. This sequence, which defines the start of the individual histone mRNAs, is preceded by the A+T-rich octanucleotide identified in front of all eukaryotic structural genes where sequences have been determined to date.

Animals↗
PubMed1998

Histone- and protamine-DNA association: conservation of different patterns within the beta-globin domain in human sperm.

Most DNA in human sperm is bound to highly basic proteins called protamines, but a small proportion is complexed with histones similar to those found in active chromatin. This raises the intriguing possibility that histones in sperm are marking sets of genes that will be preferentially activated during early development. We have examined the chromatin structure of members of the beta-globin gene family, which are expressed at different times in development, and the protamine 2 gene, which is expressed in spermatids prior to the widespread displacement of histones by transition proteins. The genes coding for epsilon and gamma globin, which are active in the embryonic yolk sac, contain regions which are histone associated in the sperm. No histone-associated regions are present at the sites tested within the beta- and delta-globin genes which are silent in the embryonic yolk sac. The trends of histone or protamine association are consistent for samples from the same person, and no significant between-subject variations in these trends are found for 13 of the 15 fragments analyzed in the two donors. The results suggest that sperm chromatin structures are generally similar in different men but that the length of the histone-associated regions can vary. The association of sperm DNA with histones or protamines sometimes changes within as little as 400 bp of DNA, suggesting that there is fine control over the retention of histones.

Binding Sites↗
PubMed1986

Different micrococcal nuclease cleavage patterns characterize transcriptionally active and inactive sea-urchin histone genes.

The micrococcal nuclease cleavage sites have been mapped in the H2A coding and flanking regions of the sea-urchin histone DNA chromatin. A hypersensitive area, centered around - 100 base pairs from the H2A starting site, is found only in embryos actively transcribing the alpha-subtype histone genes. In mesenchyme blastula embryos, upon inactivation of the H2A gene, this region becomes protected while two other areas, near the transcription starting site and in the proximity of the 3' palindromic sequence, become preferential targets for the enzyme. Analysis of the pattern of micrococcal nuclease cleavage on the same region of the histone gene cluster in sperm and late blastula chromatin and on the corresponding segment of protein-free DNA indicates that distinct nucleosomal arrangements characterize the histone genes in the two cell populations.

Animals↗