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PubMed1985

Histone gene organization of fission yeast: a common upstream sequence.

Histone genes of the fission yeast Schizosaccharomyces pombe were cloned from Charon 4A and cosmid gene libraries by hybridization, and their nucleotide sequences were determined. The genome of S. pombe has a single, isolated H2A, a pair of H2A-H2B and three pairs of H3-H4 (one H2B, two H2A and three each of H3 and H4). This non-assorted histone gene organization is distinct from that of the budding yeast which has two pairs of H2A-H2B and H3-H4. The predicted amino acid sequences of S. pombe histone H2As, H3s and H4s were identical except for three residue changes in H2As. Compared with those os S. cerevisiae and human, variable residues were clustered near the NH2- and COOH-terminal regions of H2A and H2B. Sequence homologies to the two organisms were roughly the same in H2A (79-83%), H3 (92-93%) and H4 (91%), but differed in H2B (82% to S. cerevisiae and 68% to human). The coding sequences in pairs of S. pombe histone genes were divergently directed. A 17-bp long highly homologous sequence (AACCCT box) that had internal 6-bp direct repeats was present in the intergene spacer sequences or in the 5' upstream region of all the cloned histone genes. A possible regulatory role of the common upstream sequence for histone gene expression is discussed.

Amino Acid Sequence↗
PubMed1987

Competition for formation of nucleosomes on fragmented SV40 DNA: a hyperstable nucleosome forms on the termination region.

We have studied the relative abilities of different simian virus 40 (SV40) DNA segments to reconstitute into nucleosomes in vitro. The SV40 genome was separated into 15 discrete fragments by restriction endonuclease digestion and reconstituted with calf thymus core histones under conditions of varying histone-to-DNA ratios. Three fragments show very different abilities to form nucleosomes when low histone-to-DNA ratios require all fragments to compete for available histones. Two of these fragments, both from within protein-coding regions, are significantly underreconstituted. The third fragment, covering the SV40 termination region, competes much more effectively for histones than the other 14 fragments. The fragment containing the SV40 origin region formed nucleosomes with about average probability. Overall, the SV40 fragments differed by approximately an order of magnitude in their abilities to support nucleosome formation in vitro. The stability of the nucleosomes was measured by challenge with high concentrations of the destabilizing reagent heparin. The fragment that reconstituted most effectively also formed nucleosomes that were unusually stable to heparin challenge. These observations are intriguing since this fragment contains the sequences where replication of SV40 DNA commonly terminates and where early messenger RNA synthesis may terminate as well. The existence of unique hyperstable nucleosomes in this region suggests the interesting possibility that such nucleosomes may assist in termination events by assisting in the pausing of replication or transcription complexes.

Animals↗
PubMed1978

Adenovirus core protein synthesis in the absence of viral DNA synthesis late in infection.

The acid extraction of the adenovirus type 5 core proteins V, VII, and pVII (the precursor to VII) from infected cells and the subsequent electrophoresis on a 15% acrylamide-2.5 M urea-0.9 N acetic acid (pH 2.7) gel, revealed that peptide VII has a similar electrophoretic mobility to that of histone H1. The core proteins, which are coded by late adenovirus mRNA, continued to be synthesized late in infection when viral DNA synthesis was inhibited either by cytosine arabinoside in wild-type infections or by shifting adenovirus H5 ts 125-infected cells to the nonpermissive temperature (40 degree C). Only the initiation, not the continuation, of viral DNA replication was essential for core protein synthesis. The synthesis of viral core proteins continued for over 8 h after the cassation of DNA synthesis. This was in contrast to the rapid shutdown of cellular histone synthesis in the absence of cellular DNA synthesis.

Adenoviruses, Human↗
PubMed1986

Tissue restricted and stage specific transcription is maintained within 411 nucleotides flanking the 5' end of the chicken alpha-skeletal actin gene.

alpha-skeletal actin message levels have been shown to be tightly regulated in chicken primary myoblast cultures. To test for gene elements required for muscle cell specific expression, DNA sequences containing the 5'-flanking regions of the chicken alpha-skeletal actin, beta-cytoplasmic actin, and the histone H2b genes were linked to the coding sequences of the chloramphenicol acetyltransferase gene and transfected into myogenic and non-myogenic cells. In contrast to beta-actin CAT hybrids, the alpha-skeletal actin CAT constructions displayed restricted CAT expression in transfected non-myogenic cells. We showed that a 411 nucleotide fragment flanking the 5' end of of the alpha-skeletal actin gene was responsible for a 9-15 fold increase in CAT enzymatic activity during myoblast fusion, versus only a transient 2 fold rise for the beta-actin and histone flanking sequences. These results indicate that DNA sequences within 411 bp of the 5' terminus of the alpha-skeletal actin gene influenced its cell type and stage specific expression.

Acetyltransferases↗
PubMed1994

Expression of a marked H2A histone protein in mammalian cells.

Histone protein sequences are highly conserved. In order to determine whether histones with sequences not found in nature would be tolerated in the chromatin of tissue culture cells, a gene for histone H2A.1a was altered by extending the protein coding region with eight amino acids, including three residues for methionine which are lacking in H2A.1a. Isolated clones of HeLa cells transfected with the gene construct were found to produce a novel protein which was resolved from other histone proteins on AUT-AUC two-dimensional gels. One clone, HeLa-B4, in which the novel protein named H2A.E accounted for about 10% of total H2A protein, was studied further. The linkage of H2A.E mRNA concentrations to the rates of DNA and protein synthesis was found to be the same as that of other replication-linked histone mRNA species. The stability of H2A.E in chromatin as well as the partitioning of nascent H2A.E protein between soluble and nuclear fractions was found to be indistinguishable from that of other histone species. This study shows that histone proteins with sequences other than the conserved sequences found in nature may be utilized in tissue culture cells.

Amino Acid Sequence↗
PubMed2005

Structure of allelic variants of subtype 5 of histone H1 in pea Pisum sativum L.

The pea genome contains seven histone H1 genes encoding different subtypes. Previously, the DNA sequence of only one gene, His1, coding for the subtype H1-1, had been identified. We isolated a histone H1 allele from a pea genomic DNA library. Data from the electrophoretic mobility of the pea H1 subtypes and their N-bromosuccinimide cleavage products indicated that the newly isolated gene corresponded to the H1-5 subtype encoded by His5. We confirmed this result by sequencing the gene from three pea lines with H1-5 allelic variants of altered electrophoretic mobility. The allele of the slow H1-5 variant differed from the standard allele by a nucleotide substitution that caused the replacement of the positively charged lysine with asparagine in the DNA-interacting domain of the histone molecule. A temperature-related occurrence had previously been demonstrated for this H1-5 variant in a study on a worldwide collection of pea germplasm. The variant tended to occur at higher frequencies in geographic regions with a cold climate. The fast allelic variant of H1-5 displayed a deletion resulting in the loss of a duplicated pentapeptide in the C-terminal domain.

Alleles↗
PubMed2004

Histone deacetylase inhibitors.

The base sequence of DNA provides the genetic code for proteins. The regulation of expression or suppression of gene transcription is largely determined by the structure of the chromatin--referred to as epigenetic gene regulation (Agalioti et al., 2002; Jenuwein and Allis, 2001; Richards and Elgin, 2002; Spotswood and Turner, 2002; Zhang and Reinberg, 2001). Posttranslational modifications of the histones of chromatin play an important role in regulating gene expression. Some of the most extensively studied epigenetic modifications involve acetylation/deacetylation of lysines in the tails of the core histones, which is controlled by the action of histone deacetylases (HDACs) and histone acetyltransferases (HATs). A controlled balance between histone acetylation and deacetylation appears to be essential for normal cell growth (Waterborg, 2002). Alterations in the structure or expression of HATs and HDACs occur in many cancers (Jones and Baylin, 2002; Marks et al., 2001, 2003; Timmermann et al., 2001; Wang et al., 2001). A structurally diverse group of molecules has been developed that can inhibit HDACs (HDACi) (Arts et al., 2003; Bouchain and Delorme, 2003; Curtin and Glaser, 2003; Johnstone and Licht, 2003; Marks et al., 2003; Remiszewski, 2003; Richon et al., 1998; Yoshida et al., 2003). These inhibitors induce growth arrest, differentiation, and?or apoptosis of cancer cells in vitro and in in vivo tumor-bearing animal models. Clinical trials with several of these agents have shown that certain HDACi have antitumor activity against various cancers at doses that are well tolerated by patients (Gottlicher et al., 2001; Kelly et al., 2002a,b; Piekarz et al., 2001; Wozniak et al., 1999).

Acetylation↗
PubMed2004

Evidence for nucleosome depletion at active regulatory regions genome-wide.

The identification of nuclease-hypersensitive sites in an active globin gene and in the 5' regions of fruit fly heat shock genes first suggested that chromatin changes accompany gene regulation in vivo. Here we present evidence that the basic repeating units of eukaryotic chromatin, nucleosomes, are depleted from active regulatory elements throughout the Saccharomyces cerevisiae genome in vivo. We found that during rapid mitotic growth, the level of nucleosome occupancy is inversely proportional to the transcriptional initiation rate at the promoter. We also observed a partial loss of histone H3 and H4 tetramers from the coding regions of the most heavily transcribed genes. Alterations in the global transcriptional program caused by heat shock or a change in carbon source resulted in an increased nucleosome occupancy at repressed promoters, and a decreased nucleosome occupancy at promoters that became active. Nuclease-hypersensitive sites occur in species from yeast to humans and result from chromatin perturbation. Given the conservation of sequence and function among components of both chromatin and the transcriptional machinery, nucleosome depletion at promoters may be a fundamental feature of eukaryotic transcriptional regulation.

Genes, Fungal↗
PubMed1989

Different 3'-end processing produces two independently regulated mRNAs from a single H1 histone gene.

We describe the isolation of a mouse H1 histone gene that encodes two mRNA transcripts. One mRNA ends just beyond the coding region, near a highly conserved palindrome sequence typical of cell cycle-regulated histone genes. The level of this transcript is coupled to DNA replication. The second mRNA ends nearly 1 kilobase downstream near a polyadenylation signal. This mRNA is polyadenylylated, and its accumulation is not coupled to DNA replication. The two mRNAs are regulated independently and in some circumstances in opposite directions under several physiological conditions. The production of a polyadenylylated mRNA from an otherwise cell cycle-regulated histone gene may allow for continued synthesis of the histone protein when DNA synthesis ceases in nondividing cells.

Acetamides↗
PubMed2003

A distal enhancer in the interferon-gamma (IFN-gamma) locus revealed by genome sequence comparison.

Large-scale cross-species DNA sequence comparison has become a powerful tool to identify conserved cis-regulatory modules of genes. However, bioinformatic analysis alone cannot reveal how an evolutionarily conserved region regulates gene expression: whether it functions as an enhancer, silencer, or insulator; whether its function is cell-type restricted; and whether biologically relevant transcription factors bind to the element. Here we combine bioinformatics with wet-lab techniques to illustrate a general and systematic method of identifying functional conserved regulatory regions of genes. We applied this approach to the interferon-gamma (IFN-gamma) gene. Comparison of human and mouse IFN-gamma reveals a highly conserved non-coding sequence located approximately 5 kb 5' of the transcription start site. This region coincides with constitutive and inducible DNase I hypersensitivity sites present in IFN-gamma-producing Th1 cells but not in Th2 cells that do not produce IFN-gamma. Histone methylation at the 5' conserved non-coding sequences indicates a more accessible chromatin structure in Th1 cells compared with Th2 cells. This element binds two transcription factors known to be essential for IFN-gamma expression: nuclear factor of activated T cells, an inducible transcription factor, and T-box protein expressed in T cells, a cell lineage-restricted transcription factor. Together, these findings identify a highly conserved distal enhancer in the IFN-gamma cytokine locus and validate our approach as a successful method to detect cis-regulatory elements.

Animals↗
PubMed1987

A rat histone H4 gene closely associated with the testis-specific H1t gene.

A rat histone H4 gene closely associated with the testis-specific H1t gene was isolated by screening the Sargent-Bonner rat genomic library using cloned human histone genes as probes. Both the H4 gene and the H1t gene are located on a 7-kb EcoRI genomic DNA fragment. Although the deduced amino acid sequence of the rat H4 histone is identical to that of the sequence of human histone H4, the nucleotide sequence of the coding region differs significantly from the coding region of the human H4 gene. Moreover, the relative spacing between the 5'-consensus sequence elements is unique for an H4 gene. S1-nuclease protection analyses reveal that both the H4 and H1t mRNA species are present in a fraction of rat testis cells highly enriched in pachytene spermatocytes, while only the H4 mRNA species is present in a rat myeloma cell line (Y3-Ag1.2.3). During a 1-h hydroxyurea treatment of the Y3 cells, which produces a 99% inhibition of DNA synthesis, the level of this H4 mRNA drops by only 50%, indicating that the stability of this mRNA is only partially coupled with DNA synthesis.

Amino Acid Sequence↗
PubMed1988

Histone genes in three sea star species: cluster arrangement, transcriptional polarity, and analyses of the flanking regions of H3 and H4 genes.

The arrangement of core histone genes and their transcriptional polarity has been determined for three species of sea stars (Pisaster ochraceus, P. brevispinus, and Dermasterias imbricata) representing two orders which diverged over 500 million years ago. Each species has approximately 500 core histones cluster repeats per haploid genome. The close phylogenetic relationship between the Pisaster species is evident from the correspondence of restriction sites in the repeat element, identical arrangement of core histones, and high degree of sequence homology in both the coding and spacer regions of the H3 gene. The Dermasterias repeat has the same gene order and transcriptional polarity of core histones, but its restriction map is significantly different. Moreover, the Dermasterias H3 gene has the same amino acid sequence, but in comparison to Pisaster nucleotide sequences, shows a high level of silent substitutions. Analyses of the nucleotide sequence of the 5' and 3' regions surrounding the H3 gene from each species demonstrate the presence of appropriately spaced consensus and processing signal segments. The 3' spacer segment of the Dermasterias H4 gene contains an unusual, threefold tandemly repeated, 21-nucleotide, AT-rich sequence. No similar sequence is seen in the P. brevispinus H4 3' region, but these two species show a striking regularity of distribution of five different homologous oligomers in the 3' spacer.

Animals↗
PubMed2005

Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast.

We have conducted a genomewide investigation into the enzymatic specificity, expression profiles, and binding locations of four histone deacetylases (HDACs), representing the three different phylogenetic classes in fission yeast (Schizosaccharomyces pombe). By directly comparing nucleosome density, histone acetylation patterns and HDAC binding in both intergenic and coding regions with gene expression profiles, we found that Sir2 (class III) and Hos2 (class I) have a role in preventing histone loss; Clr6 (class I) is the principal enzyme in promoter-localized repression. Hos2 has an unexpected role in promoting high expression of growth-related genes by deacetylating H4K16Ac in their open reading frames. Clr3 (class II) acts cooperatively with Sir2 throughout the genome, including the silent regions: rDNA, centromeres, mat2/3 and telomeres. The most significant acetylation sites are H3K14Ac for Clr3 and H3K9Ac for Sir2 at their genomic targets. Clr3 also affects subtelomeric regions which contain clustered stress- and meiosis-induced genes. Thus, this combined genomic approach has uncovered different roles for fission yeast HDACs at the silent regions in repression and activation of gene expression.

Acetylation↗
PubMed1996

Mapping of DNA-binding proteins along the yeast genome by UV-induced DNA-protein crosslinking.

UV-induced crosslinking of DNA-binding proteins to DNA in intact nuclei of Saccharomyces cerevisiae and subsequent 'protein image' hybridization were applied to map non-histone proteins along single-copy genes of yeast. We detected two polypeptides that most probably correspond to core subunits of yeast RNA-polymerase II in the coding region of transketolase gene (TKL2). Several non-histone proteins were also detected which bind to the upstream region of TKL2 gene, and to the intergenic spacer between calmodulin (CMD1) and beta-mannosyl transferase (ALG1) genes.

Calmodulin↗
PubMed1987

Characterization of two types of histone H2B genes from macronuclei of Tetrahymena thermophila.

Two histone H2B gene clones were isolated from macronuclei of Tetrahymena thermophila. Nucleotide sequences of the two clones were highly homologous within the coding region but not in the noncoding region. Comparison of the deduced amino acid sequences between the two clones showed three differences in a total of 121 amino acids. Each of the two clones contained a TAA triplet within the coding region, which appeared to code for a glutamine residue. To demonstrate the existence of histone mRNA containing UAA triplet, nuclease P1 protection mapping using total cellular RNA and nucleotide sequencing of primer extension products were carried out. The results clearly indicated that two cloned histone H2B genes were transcribed, giving rise to the major histone H2B mRNAs with a UAA triplet sequence in frame. The tentative 5'- and 3'-ends of histone H2B mRNAs were determined.

Amino Acid Sequence↗
PubMed2006

Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins.

Polycomb group (PcG) and trithorax group (trxG) proteins act as antagonistic regulators to maintain transcriptional OFF and ON states of HOX and other target genes. To study the molecular basis of PcG/trxG control, we analyzed the chromatin of the HOX gene Ultrabithorax (Ubx) in Ubx(OFF)and Ubx(ON)cells purified from developing Drosophila. We find that PcG protein complexes PhoRC, PRC1, and PRC2 and the Trx protein are all constitutively bound to Polycomb response elements (PREs) in the OFF and ON state. In contrast, the trxG protein Ash1 is only bound in the ON state; not at PREs but downstream of the transcription start site. In the OFF state, we find extensive trimethylation at H3-K27, H3-K9, and H4-K20 across the entire Ubx gene; i.e., throughout the upstream control, promoter, and coding region. In the ON state, the upstream control region is also trimethylated at H3-K27, H3-K9, and H4-K20, but all three modifications are absent in the promoter and 5' coding region. Our analyses of mutants that lack the PcG histone methyltransferase (HMTase) E(z) or the trxG HMTase Ash1 provide strong evidence that differential histone lysine trimethylation at the promoter and in the coding region confers transcriptional ON and OFF states of Ubx. In particular, our results suggest that PRE-tethered PcG protein complexes act over long distances to generate Pc-repressed chromatin that is trimethylated at H3-K27, H3-K9, and H4-K20, but that the trxG HMTase Ash1 selectively prevents this trimethylation in the promoter and coding region in the ON state.

Animals↗
PubMed2001

TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast.

TUP1 is recruited to and represses genes that regulate mating, glucose and oxygen use, stress response, and DNA damage. It is shown here that disruption of either TUP1 or histone deacetylase HDA1 causes histone H3/H2B--specific hyperacetylation next to the TUP1 binding site at the stress-responsive ENA1 promoter. It is also shown that TUP1 interacts with HDA1 in vitro. These data indicate that TUP1 mediates localized histone deacetylation through HDA1. Interestingly, RPD3 deacetylates the ENA1 coding region, and both deacetylases contribute to ENA1 repression. However, epistasis analysis argues that only HDA1 and TUP1 are likely to function in the same pathway. These data define gene and histone targets of HDA1 and illustrate the role of histone deacetylation in TUP1 repression.

ATP-Binding Cassette Transporters↗