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PubMed1986

The beta-globin domain in immature chicken erythrocytes: enhanced solubility is coincident with histone hyperacetylation.

A 60 minute exposure of chicken immature erythrocytes to n-butyrate shifts actively acetylated and deacetylated histones to hypermodified forms. Micrococcal nuclease digestion of nuclei from n-butyrate treated cells and subsequent fractionation of the chromatin releases 40-45% of the adult beta-globin (beta A) nucleohistone into a soluble fraction. This is an eleven fold enrichment over the soluble chromatin from untreated cells (Ferenz and Nelson (1985) Nucleic Acids Res. 13, 1977-1995). The enhanced beta A chromatin solubility and induced histone hyperacetylation are coincident. Removal of n-butyrate from the cell incubation medium allows rapid histone deacetylation and a striking reduction in beta A chromatin solubility. Chromatin from cells incubated in the absence of n-butyrate, or in medium containing 10 mM NaCl or 2% dimethylsulfoxide, does not exhibit histone hyperacetylation, or the acquired solubility of beta A chromatin. We show that the H4 histone co-isolated with the beta A DNA is in a hyperacetylated state and present evidence that the n-butyrate incubation increases the solubility of both coding and noncoding chromatin regions in the beta-globin domain.

Acetylation↗
PubMedDate not supplied

Cloning and analysis of the Kluyveromyces lactis TRP1 gene: a chromosomal locus flanked by genes encoding inorganic pyrophosphatase and histone H3.

The TRP1 gene of the yeast Kluyveromyces lactis has been cloned from a genomic library by complementation of the Saccharomyces cerevisiae trp1-289 mutation. The gene was located within the clone by transposon mutagenesis and the coding region identified by DNA sequencing. This has indicated that K. lactis TRP1 encodes a 210-amino acid polypeptide which shows 53% identity to the homologous S. cerevisiae protein. The K. lactis TRP1 gene has been disrupted by substituting the S. cerevisiae URA3 gene for a large part of the TRP1 coding sequence. Replacement of the chromosomal TRP1 locus with this construction has enabled the production of non-reverting trp1- strains of K. lactis, while a genetic analysis of the disrupted allele confirmed that the TRP1 gene had been cloned. DNA sequencing has also shown that the K. lactis TRP1 sequence is flanked by genes encoding inorganic pyrophosphatase and histone H3, which we have designated IPP and HHT1 respectively. Hybridization studies have shown that in common with S. cerevisiae, K. lactis has two copies of the histone H3 gene. Each H3 gene is closely linked to a gene encoding histone H4 and in both yeast species the IPP gene is tightly linked to one of the histone gene pairs.

Amino Acid Sequence↗
PubMedDate not supplied

[Gradient condensation of chromatin in ribosomal genes of Drosophila melanogaster].

The organization of chromatin in D. melanogaster ribosomal repeats with and without insertions was studied. We have shown earlier that upon digestion with micrococcal nuclease a "non-transcribed" intergenic spacer produces unusual chromatin particles containing DNA fragments 200-280 b.p. in length. These particles sediment like H1-containing nucleosomes, are stable only in the presence of polyamines, and are probably bound to some non-histone protein. The content of core histones and H1 in different regions of ribosomal genes has been studied by two-dimensional electrophoresis of chromatin particles and by "protein-image" hybridization. The content of histones and respectively the degree of chromatin condensation increase in the following order: the 1kb-long region surrounding the initiation site is practically free of histones less than the region of 240 b.p. repeats from the intergenic spacer, containing homologies with the ribosomal promotor less than coding region preceding the usual site of insertions less than coding region lying behind this site less than inactive type II ribosomal insertion. Therefore, the region of the beginning of transcription of most ribosomal genes is in an active conformation, even though at least 75% of the genes are repressed. Ribosomal insertions are in a compact, repressed form. We suggest that their inhibitory action on the transcription of corresponding genes at the molecular level is similar to the position effect of heterochromatic regions at the chromosomal level.

Animals↗
PubMed1989

In vivo protein binding sites and nuclease hypersensitivity in the promoter region of a cell cycle regulated human H3 histone gene.

The chromatin structure and protein-DNA interactions of a cell cycle regulated human H3 histone gene have been examined at different levels of resolution. Using traditional Southern blot analysis we have investigated the accessibility of the H3 coding region and its flanking sequences to DNase I, S1 nuclease and restriction endonuclease digestion. Using the native genomic blotting method recently developed in our laboratory, two sites of protein-DNA interaction in the proximal 240 bp of the promoter region of this H3 gene were established. Further in vivo analysis of protein-DNA binding sites in intact cells by genomic sequencing revealed, with single nucleotide resolution, the guanine contacts and footprints of the proteins bound to the promoter. The relative locations of protein-DNA interactions in this H3 gene are similar to those identified in vivo and in vitro in a cell cycle dependent human H4 histone gene. The proteins complexed with the H3 histone gene promoter can be dissociated between 0.16 and 0.28 M NaCl. The protein-DNA contacts persist throughout the cell cycle and thus may have a functional relationship with the basal level of transcription of this H3 gene that occurs during and outside of S phase.

Base Sequence↗
PubMed1980

Transcriptional fidelity of histone genes injected into Xenopus oocyte nuclei.

Previous work has indicated that at least some of the genetic information required for the expression of sea urchin histone genes is recognized following injection of the gene repeat (h22) into Xenopus oocyte nuclei. The ability to elicit the expression of cloned genes and their sequence-manipulated counterparts is proving invaluable in analysing the molecular details of gene expression. Direct injection of such genes into Xenopus oocyte nuclei remains one of the simplest methods for obtaining such expression and a remarkable degree of transcriptional fidelity has been demonstrated using this system with RNA polymerase III genes, and to a lesser extent with rDNAs transcribed by RNA polymerase I. In the case of polymerase II genes there is ample evidence for coupled transcription-translation, but the degree of transcriptional fidelity involved may, as has recently been shown for the ovalbumin gene, be minimal. However, clearly if the oocyte is to be used to investigate transcriptional regulation of such genes, transcriptional fidelity defined as the production of correct RNA termii, rather than the production of 'functional mRNAs' (ref. 15), must pertain. Here we demonstrate such fidelity in the expression of all five Psammechinus miliaris histone genes comprising a repeat unit. However, we find large quantitative variations in the levels of synthesis of the individual correct termini and hence of the mRNAs. In addition to the mRNAs, species with no detectable counterparts in the sea urchin are generated off the coding strand, as are heterogeneous noncoding species.

Animals↗
PubMed1993

Two histone H1-encoding genes of the green alga Volvox carteri with features intermediate between plant and animal genes.

Southern hybridization indicated the presence of at least two and possibly four histone H1-encoding genes occurring as singlets in the Volvox carteri genome. Two of these genes, H1-I and H1-II, have been cloned and characterized. Their coding sequences are each interrupted by three introns, but only the position of the second intron is identically conserved in both H1-I and H1-II. The encoded 260-amino-acid (aa) (H1-I) and 240-aa (H1-II) polypeptides possess the typical tripartite organization of animal H1 histones, with variable N- and C-terminal domains flanking a conserved 'globular' DNA-binding domain. Extensive differences in their variable regions suggest that H1-I and H1-II (62% identity) represent two isotypes with different functions. A prominent KAPKAP-KAA motif in the H1-I N-terminal region, similarly seen in single H1 variants of a mosquito and a nematode, has a putative function in packing condensed subtypes of chromatin. Different from higher plants, but like animals, the H1 genes of V. carteri possess a typical 3' palindrome for mRNA processing, resulting in non-polyadenylated mRNAs. Transcription initiates 33 nucleotides (nt) (H1-I) and 26 nt (H1-II) downstream of typical TATA boxes. A putative 20-bp conserved enhancer element upstream of each TATA box closely resembles the consensus sequence associated with the nucleosomal histone-encoding genes in V. carteri [Müller et al., Gene 93 (1990) 167-175] and suggests stringent regulation. Accordingly, transcription of H1 was shown to be restricted to late embryogenesis, when new flagella are produced. We discuss the inferred accessory role of histone H1 proteins in stabilizing axonemal microtubules, as has been recently observed in sea urchin flagella [Multigner et al., Nature 360 (1992) 33-39].

Amino Acid Sequence↗
PubMed1986

Normal stoichiometry of histone dimer sets is necessary for high fidelity of mitotic chromosome transmission.

To identify gene products that function stoichiometrically in mitotic chromosome transmission, genes were cloned on high copy number plasmids and transformed into yeast cells, and the transformants were examined for an increase in the frequency of mitotic chromosome loss or recombination resulting from the gene imbalance. When either pair of the yeast histone genes H2A and H2B, or H3 and H4 was present on high copy number plasmids, both chromosomes V and VII exhibited an increased frequency of chromosome loss. The rate of chromosome loss was not elevated when the histone genes were present on single copy plasmids, when their transcription from high copy plasmids was repressed, or when frame-shift mutations were present in the coding sequence. This method for the identification of genes circumvents some of the limitations of traditional mutational analysis and yields the cloned gene.

Aneuploidy↗
PubMed1994

Isolation and characterization of two replication-dependent mouse H1 histone genes.

Mice contain at least seven nonallelic forms of the H1 histones, including the somatic variants H1a-e and less closely related variants H1 degrees and H1t. The mouse H1 degrees and H1c (H1var.1) genes were isolated and characterized previously. We have now isolated, sequenced and studied the expression properties of two additional mouse H1 genes, termed H1var.2 and H1var.3. Extensive amino acid and nucleotide sequence comparisons were made between the two genes and other mammalian H1 histone genes. A high degree of nucleotide sequence identity was seen between the H1var.2, rat H1d and human H1b genes, even well beyond the coding region, indicating that these genes are likely homologues. Unlike the previously characterized mouse H1var.1 gene which produces both nonpolyadenylated and polyadenylated mRNAs, the H1var.2 and H1var.3 genes produce only typical, replication dependent, nonpolyadenylated mRNAs.

Amino Acid Sequence↗
PubMed1987

Characterization of the chicken histone H1 gene complement. Generation of a complete set of vertebrate H1 protein sequences.

Sequence analysis of four chicken H1 histone genes described here completes the characterization of the full complement of six H1 genes in the chicken genome. Each of the six genes codes for a different H1 protein sequence, and these range in size from 217 to 224 amino acids. The proteins are distinct in sequence from the H1-related chicken H5 protein and appear to be analogous to the standard somatic mammalian H1 subtypes. The protein sequence data deduced from the genes represent the first complete set of vertebrate H1 protein sequences. Comparison of the chicken H1 gene noncoding sequences with each other and with H1 gene sequences from other organisms reveals conservation of an H1 gene-specific element, a G-rich element, and histone gene-specific 3' elements. Additional sequences are conserved between H1 genes of the chicken and other vertebrates. Comparisons also reveal variation in promoter and 3' elements between chicken genes that could play a role in the differential expression of H1 gene protein products.

Amino Acid Sequence↗
PubMed1983

Synthesis of yeast histone 3 in an Escherichia coli cell-free system.

The gene for histone H3 from the yeast Saccharomyces cerevisiae was placed under the control of the lac promoter of Escherichia coli by fusing the H3 coding sequence to that of beta-galactosidase. The gene was shown to be transcribed in vivo, but its product was not detected in cell extracts. However, synthesis of the fused polypeptide was detected in an in vitro transcription-translation system derived from E. coli. Proteolytic degradation of the newly synthesized polypeptides may be the cause of their apparent absence in the in vivo experiment.

Amino Acid Sequence↗
PubMed1997

Differential expression of the murine histone genes H3.3A and H3.3B.

The histone family of proteins is subdivided into two major groups: the main type histones, which are synthesized in coordination with DNA replication during the S-phase of the cell cycle, and the replacement histones, which can be synthesized in the absence of DNA replication substituting main type histone isoforms. Accumulation of replacement histone variants has been observed in several terminally differentiated tissues that have stopped cell division. The replacement subtype of the H3 class is termed H3.3. This protein is encoded by two different genes (H3.3A and H3.3B) that both code for the same amino acid sequence, but differ in nucleotide sequences and gene organization. This has been shown for human and avian H3.3A and H3.3B genes and for a murine H3.3B cDNA. In an attempt to define patterns of replacement histone H3.3 gene expression during male germ cell differentiation, we have constructed mouse testicular cDNA libraries and have isolated cDNAs corresponding to the murine H3.3A and H3.3B genes. Using probes specific for these two different genes we show by RNase protection analysis and by nonradioactive in situ hybridization with testis sections that H3.3A mRNA is present in pre- and postmeiotic cells, whereas expression of the H3.3B gene is essentially restricted to cells of the meiotic prophase.

Amino Acid Sequence↗
PubMed2000

Origin and persistence of the mitochondrial genome.

The mitochondrial genome comprises a circular, histone-free 'chromosome' of 16.6 kb of DNA, present in one or more copies in every mitochondrion. This chromosome has been tightly conserved for more than half a billion years, coding in every multicellular animal so far investigated, both vertebrate and invertebrate: (i) the same 13 protein subunits required for oxidative phosphorylation; (ii) a component of each of the two mitochondrial ribosome subunits; and (iii) the 22 transport RNAs present within the mitochondrion. Exons on the circle are tightly packed, with no spacing introns. Mitochondrial DNA is histone-free, has limited repair ability, and has a relatively high mutation-fixation rate. Inheritance is cytoplasmic and maternal, with epidemiological evidence (namely the familial distribution of polymorphisms) indicating that recombination with mtDNA of paternal origin is exceedingly rare. Thus the maintenance and evolution of mtDNA (its remarkably successful symbiotic persistence with the nuclear genome) has been essentially asexual. The machinery for homologous recombination is present in mitochondria of at least some species, however, and it might be surprising if it did not occur between circles in some circumstances. By bringing together the fields of mitochondrial biochemistry, evolutionary genetics, reproductive physiology, and neuromuscular medicine in focusing on the inheritance of normal and abnormal human mtDNA, we can hope to better understand the forces behind this genome's inheritance and what might be required of ovarian function to satisfy its accurate persistence over millions of years. Clinically we can hope also for a better understanding of ooplasmic factors in human fertility and in the wide manifestations of mitochondrial genomic disease.

Animals↗
PubMed2003

Modelling study on the protective role of OH radical scavengers and DNA higher-order structures in induction of single- and double-strand break by gamma-radiation.

PURPOSE: To quantify the protective effects of (non-histonic) OH-radical scavengers and DNA higher-order structures in induction of single- (ssbs) and double-strand breaks (dsbs) by gamma-rays. MATERIALS AND METHODS: Spatial distributions of energy depositions by gamma-rays in liquid water were modelled with the track structure modules of the biophysical simulation code PARTRAC. Such distributions were superimposed on different DNA structure models (e.g. linear DNA, SV40 'minichromosomes' and compact chromatin), and direct energy depositions in the sugar-phosphate were considered as potential (direct) ssbs. The diffusion and interaction of the main chemical species produced in liquid water radiolysis were explicitly simulated, and reactions of *OH with the sugar-phosphate were considered as potential (indirect) ssbs. Two ssb on opposite DNA strands within 10 base pairs were considered as one dsb. Yields of ssb and dsb Gy(-1) Dalton(-1) in different DNA target structures were calculated as a function of the *OH mean lifetime, whose inverse value was taken as representative of the scavenging capacity of the DNA environment. RESULTS AND CONCLUSIONS: A further validation of the models implemented in the PARTRAC code has been provided, thus allowing a better understanding of the mechanisms underlying DNA damage. More specifically, the protection due to *OH scavengers was separately quantified with respect to that due to histones and chromatin folding, which could be 'switched off' in the simulations. As expected, for a given value of the environment scavenging capacity, linear DNA was more susceptible to strand breakage than SV40 minichromosomes, which in turn showed higher damage yields with respect to cellular DNA due to the larger accessibility offered to *OH. Furthermore, by increasing the scavenging capacity, the break yields decreased in all structures and tended to coincide with direct damage yields. Very good agreement was found with available experimental data. Comparisons with data on 'nucleoid' DNA (i.e. unfolded and histone-depleted DNA) also suggested that the experimental procedures used to obtain such structures might lower the environment scavenging capacity owing to the loss of cellular scavengers.

DNA↗
PubMed2001

Yeast chromatin structure and regulation of GAL gene expression.

Yeast genomic DNA is covered by nucleosome cores spaced by short, discrete length linkers. The short linkers, reinforced by novel histone properties, create a number of unique and dynamic nucleosome structural features in vivo: permanent unpeeling of DNA from the ends of the core, an inability to bind even full 147 bp core DNA lengths, and facility to undergo a conformational transition that resembles the changes found in active chromatin. These features probably explain how yeast can maintain most of its genome in a transcribable state and avoid large-scale packaging away of inactive genes. The GAL genes provide a closely regulated system in which to study gene-specific chromatin structure. GAL structural genes are inactive without galactose but are highly transcribed in its presence; the expression patterns of the regulatory genes can account for many of the features of GAL structural gene control. In the inactive state, GAL genes demonstrate a characteristic promoter chromosomal organization; the major upstream activation sequence (UASG) elements lie in open, hypersensitive regions, whereas the TATA and transcription start sites are in nucleosomes. This organization helps implement gene regulation in this state and may benefit the organism. Induction of GAL expression triggers Gal4p-dependent upstream nucleosome disruption. Disruption is transient and can readily be reversed by a Gal80p-dependent nucleosome deposition process. Both are sensitive to the metabolic state of the cell. Induction triggers different kinds of nucleosome changes on the coding sequences, perhaps reflecting the differing roles of nucleosomes on coding versus promoter regions. GAL gene activation is a complex process involving multiple Gal4p activities, numerous positive and negative cofactors, and the histone tails. DNA bending and chromosomal architecture of the promoter regions may also play a role in GAL regulation. Regulator-mediated competition between nucleosomes and the TATA binding protein complex for the TATA region is probably a central aspect of GAL regulation and a focal point for the numerous factors and processes that contribute to it.

Chromatin↗
PubMed1997

The characterization of novel Pax genes of the sea urchin and Drosophila reveal an ancient evolutionary origin of the Pax2/5/8 subfamily.

The developmental control genes of the Pax family can be grouped into different subclasses according to structure and sequence homology. Here we describe the isolation and characterization of three novel Pax genes of the sea urchin for which no homologues are yet known in other animal phyla. One of these genes, suPaxB, codes for the previously characterized transcription factor TSAP which is involved in the developmental regulation of two pairs of late histone genes. Furthermore, conserved members of the Pax2/5/8 subfamily, which have so far been described only in vertebrates, were isolated not only from the sea urchin, but also from Drosophila and C. elegans. Hence, the Pax2/5/8 transcription factors constitute an ancient subfamily of highly conserved Pax proteins. During Drosophila embryogenesis, the Pax258 gene is shown to be expressed in the precursor cells of the external sensory organs, thus suggesting a role for Pax258 in the early development of the peripheral nervous system of insects.

Amino Acid Sequence↗
PubMed1986

A chimeric mouse histone H4 gene containing either an intron or poly(A) addition signal behaves like a basal histone.

We have modified the basic structure of the mouse H4 histone gene by introducing, in one case, the IVS-II of the human beta globin gene in the middle of the H4 coding region and, in the second case, the poly(A) addition signal from either the chicken vimentin gene or the alpha globin gene, displacing the hairpin loop structure in the 3' direction. Constructs were placed into the vector, PSV2gpt, and stably transformed into L cells. Pools of 100-500 independent transformants were analyzed for H4 expression. Even though the intron is processed correctly, the growth regulated expression of the modified gene is lost and the gene is now expressed at a constant basal level. Furthermore, unprocessed transcripts accumulate in the nucleus of Go cells when compared to exponentially growing cultures. Polyadenylated H4 RNA is correctly processed but expressed at reduced levels (30 fold) in a constitutive manner, independent of the growth state of the cell. The altered expression of these chimeric H4 genes compared to the endogenous copy or the transfected wild type gene suggests a structural model to explain the cell cycle independent expression of the basal histones.

Animals↗
PubMed1997

Tandem arrangement of two genes encoding kinetoplast-associated H1 histone-like proteins.

Crithidia fasciculata proteins p18 and p17 are associated with kinetoplast DNA and are encoded by genes KAP2 and KAP3, respectively. Polymerase chain reaction (PCR) amplification using primers within the coding sequences of each gene revealed that the KAP2 and KAP3 genes are linked on the same chromosomal DNA and are separated by a 1.8 kb intergenic region containing several long homopolymer tracts. The KAP2 gene has a 3'UTR of more than 1.1 kb or almost three times as long as the KAP2 coding sequence. Several restriction enzyme polymorphisms in this region of the chromosome are the result of sequence differences between the two alleles of the KAP2 gene. The predicted amino-acid sequences of alleles KAP2-1 and KAP2-2 differ by three non-conservative amino acid substitutions in the highly basic carboxyl tail of the protein and suggest that the protein products could have different physical and biological properties. The KAP2 and KAP3 genes have different patterns of mRNA expression during the cell cycle with the KAP3 transcript varying periodically during the cell cycle in the same manner as transcripts of several kinetoplast and nuclear DNA replication genes.

Alleles↗
PubMed1985

Faithful cell-cycle regulation of a recombinant mouse histone H4 gene is controlled by sequences in the 3'-terminal part of the gene.

We have analyzed the expression of endogenous histone H4 genes and of a newly introduced H4 gene in 21-Tb cells, a mouse mastocytoma cell-cycle mutant. Endogenous H4 mRNAs were less abundant by a factor of 120-180 in G1-arrested than in exponentially multiplying cells. However, H4 transcription rates were only decreased by a factor of 3 under these conditions, as determined by in vitro elongation of nascent transcripts. This indicates that post-transcriptional control of histone mRNA levels is important, in accord with published data. We introduced a mouse H4 gene, modified by a 12-base-pair (bp) insertion in its coding sequence, into 21-Tb cells by DNA-mediated gene transfer. The levels of transcripts from this gene were regulated in parallel with those of the endogenous genes. Moreover, fusion of the simian virus 40 (SV40) early promoter to a 463-bp fragment containing the 3'-terminal half of the mouse H4 gene, including 230 bp of spacer sequences, led to the regulated expression of SV40/H4 fusion RNA. However, a small proportion of SV40-initiated transcripts were not processed to histone-specific 3' ends, but extended farther through the downstream Escherichia coli galactokinase gene to a SV40 polyadenylylation site. In contrast to the short SV40/H4 RNA, the levels of these longer transcripts were not reduced in G1-arrested cells. These results show that sequences in the 3'-terminal part of the H4 gene can regulate gene expression in the cell cycle, presumably at the post-transcriptional level, as long as they are not positioned much more distant from the terminus than normal.

Animals↗