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PubMed1984

Evolving sea urchin histone genes--nucleotide polymorphisms in the H4 gene and spacers of Strongylocentrotus purpuratus.

We present a comparison of spacer and coding sequences of histone gene repeats from four Strongylocentrotus purpuratus individuals. Sequences of two previously cloned units (pCO2 and pSp2) were compared with three new histone gene clones, two of them from a single individual. Within a 1.7-kb region, 59 polymorphic sites were found in spacers, in mRNA nontranslated stretches, and at silent sites in codons of the H4 gene. The permitted silent-site changes were as frequent as in any other region studied. The most abundant polymorphisms were single-base substitutions. The ratio of transitions : transversions : single-base-pair insertions/deletions was 3:2:2. A number of larger insertions/deletions were found, as well as differences in the length of (CTA)n and (CT)n runs. Two of the five cloned repeats contained an insertion of a 195-bp element that is also present at many other sites in the genomes of every S. purpuratus individual studied. Pairwise comparisons of the different clones indicate that the variation is not uniformly divergent, but ranges from a difference of 0.34% to 3.0% of all nucleotide sites. A parsimonious tree of ancestry constructed from the pairwise comparisons indicates that recombination between the most distantly related repeats has not occurred in the 1-2 million years necessary for accumulation of the variation. The level of sequence variation found within the S. purpuratus population, for both tandemly repeated and single-copy genes, is 25%-50% of that found between S. purpuratus and S. drobachiensis.

Alleles↗
PubMed2002

Histone gene complement, variant expression, and mRNA processing in a urochordate Oikopleura dioica that undergoes extensive polyploidization.

Considerable data exist on coding sequences of histones in a wide variety of organisms. Much more restricted information is available on total histone gene complement, gene organization, transcriptional regulation, and histone mRNA processing. In particular, there is a significant phylogenetic gap in information for the urochordates, a subphylum near the invertebrate-vertebrate transition. In this study, we show that the appendicularian Oikopleura dioica has a histone gene complement that is similar to that of humans, though its genome size is 40- to 50-fold smaller. At a total length of 3.5 kb, the H3, H4, H1, H2A, and H2B quintet cluster is the most compact described thus far, but despite very rapid early developmental cleavage cycles, no extensive tandem repeats of the cluster were present. The high degree of variation within each of the complements of O. dioica H2A and H2B subtypes resembled that found in plants as opposed to more closely related vertebrate and invertebrate species, and developmental stage-specific expression of different subtypes was observed. The linker histone H1 was present in relatively few copies per haploid genome and contained short N- and C-terminal tails, a feature similar to that of copepods but different from many standard model organisms. The 3'UTRs of the histone genes contained both the consensus stem-loop sequence and the polyadenylation signals but lacked the consensus histone downstream element that is involved in the processing of histone mRNAs in echinoderms and vertebrates. Two types of transcripts were found, i.e., those containing both the stem-loop and a polyA tail as well as those cleaved at the normal site just 3' of the stem-loop. The O. dioica data are an important addition to the limited number of eukaryotes for which sufficiently extensive information on histone gene complements is available. Increasingly, it appears that understanding the evolution of histone gene organization, transcriptional regulation, and mRNA processing will depend at least as much on comparative analysis of constraints imposed by certain life history features and cell biological characteristics as on projections based on simple phylogenetic relationships.

Amino Acid Sequence↗
PubMed2003

A human globin enhancer causes both discrete and widespread alterations in chromatin structure.

Gene activation requires alteration of chromatin structure to facilitate active transcription complex formation at a gene promoter. Nucleosome remodeling complexes and histone modifying complexes each play unique and interdependent roles in bringing about these changes. The role of distant enhancers in these structural alterations is not well understood. We studied nucleosome remodeling and covalent histone modification mediated by the beta-globin locus control region HS2 enhancer at nucleosome-level resolution throughout a 5.5-kb globin gene model locus in vivo in K562 cells. We compared the transcriptionally active locus to one in which HS2 was inactivated by mutations in the core NF-E2 sites. In contrast to inactive templates, nucleosomes were mobilized in discrete areas of the active locus, including the HS2 core and the proximal promoter. Large differences in restriction enzyme accessibility between the active and inactive templates were limited to the regions of nucleosome mobilization, which subsumed the DNase I hypersensitive sites. In contrast to this discrete pattern, histone H3 and H4 acetylation and H3 K4 methylation were elevated across the entire active locus, accompanied by depletion of linker histone H1. The coding region of the gene differed from the regulatory regions, demonstrating both nucleosome mobilization and histone hyperacetylation, but lacked differences in restriction enzyme accessibility between transcriptionally active and inactive genes. Thus, although the histone modification pattern we observe is consistent with the spreading of histone modifying activity from the distant enhancer, the pattern of nucleosome mobilization is more compatible with direct contact between an enhancer and promoter.

Acetylation↗
PubMed1994

Isolation and characterization of the gene encoding histone H2A from Trypanosoma cruzi.

In the present paper we report the isolation and characterization of the sequence of two genomic DNA fragments coding for the histone H2A of Trypanosoma cruzi. An analysis of the predicted amino acid sequence shows the presence of the amino-terminal motif characteristic of the H2A histones proteins and the Lys-Lys motif reported to be the site for the ubiquitin attachment. Southern blots of total parasite DNA probed with the H2A sequence suggested that the T. cruzi histone H2A gene is encoded in two independent gene clusters. The molecular karyotyping of the parasite indicated that these two clusters locate in a single chromosome of about 700 kb in length. The T. cruzi H2A mRNA is polyadenylated as are the basal histone mRNAs of higher eukaryotes and the histone mRNAs of yeast. By polymerase chain reaction amplification and sequencing and by S1 mapping we determined respectively the 5' and 3' end of the gene showing that the miniexon is added to the mRNA 71 nucleotides upstream of the ATG initiation codon and that the polyadenylation site locates in nucleotide position 773-775 close to invert repeats.

Amino Acid Sequence↗
PubMed1983

The primary structure and expression of four cloned human histone genes.

The complete nucleotide sequence of four human histone genes has been determined. Each gene codes for a core histone protein which is very homologous with the corresponding calf thymus of rat histones. The 5' and 3' flanking regions of the human histone genes contain previously identified concensus sequences: the TATA box, the GACTTC element; the CCAAT sequence; the 3' terminal dyad symmetry element thought to be involved in transcription termination; and a recently identified H2b specific upstream sequence. A putative H2a specific upstream sequence 5'-TTCTTGGACTCCTCTTTTC-3' is present approximately 40 base pairs upstream from the TATA box in the human H2a gene promoter. Nuclease S1 analysis of the human histone mRNAs encoded within each of these clones demonstrates that the mRNA terminii map to the expected positions relative to the known concensus sequences, and that the abundance of each mRNA is regulated during the HeLa cell cycle. Finally, in contrast to the H2b, H3 and H4 mRNAs encoded within clones pHh 4A/pHh4C, pHh5B and pHu4A, respectively, the H2a mRNA encoded by Hh5G is not present in human placental RNA.

Amino Acid Sequence↗
PubMed1976

Molecular analysis of the histone gene cluster of Psammechinus miliaris: I. Fractionation and identification of five individual histone mRNAs.

The electrophoretic separation of labeled "9S" histone mRNAs obtained from cleaving sea urchin polysomes was found at first to be highly unreproducible. It became evident that the secondary structure of the individual mRNAs had a greater effect on their relative electrophoretic mobilities than did their molecular weight differentials. We determined the parameters affecting electrophoretic mobility by the novel method of running the labeled polysomal RNA in slab gels across polyacrylamide and urea gradients. The initially complex and species-specific electrophoretic pattern could then, by a judicious choice of denaturing conditions, be simplified to yield five well defined classes of labeled mRNAs. Using optimal conditions for the separation of the RNA components, five messengers were isolated from Psammechinus embryos by preparative disc electrophoresis, four of which, after two electrophoretic separations, exhibited a unimodal distribution. Each of the mRNAs was translated in vitro, four of the five fractions promoting the synthesis of one major protein. The in vitro products were characterized by comparison of their electrophoretic mobilities with those of known sea urchin histones. It was thus possible to correlate individual mRNAs with specific histones. We propose that the five mRNAs designated a-e in order of decreasing electrophoretic mobility code for the histones H4, H2A, H2B, H3, and H1.

Animals↗
PubMed1991

A common transcriptional activator is located in the coding region of two replication-dependent mouse histone genes.

There is a region in the mouse histone H3 gene protein-encoding sequence required for high expression. The 110-nucleotide coding region activating sequence (CRAS) from codons 58 to 93 of the H3.2 gene restored expression when placed 520 nucleotides 5' of the start of transcription in the correct orientation. Since identical mRNA molecules are produced by transcription of the original deletion gene and the deletion gene with the CRAS at -520, effects of the deletions on mRNA stability or other posttranscriptional events are completely ruled out. Inversion of the CRAS sequence in its proper position in the H3 gene resulted in only a threefold increase in expression, and placing the CRAS sequence 5' of the deleted gene in the wrong orientation had no effect on expression. In-frame deletions in the coding region of an H2a.2 gene led to identification of a 105-nucleotide sequence in the coding region between amino acids 50 and 85 necessary for high expression of the gene. Additionally, insertion of the H3 CRAS into the deleted region of the H2a.2 gene restored expression of the H2a gene. Thus, the CRAS element has an orientation-dependent, position-independent effect. Gel mobility shift competition studies indicate that the same proteins interact with both the H3 and H2a CRAS elements, suggesting that a common factor is involved in expression of histone genes.

Animals↗
PubMedDate not supplied

[The loss of CpG dinucleotides from DNA. III. Methylation and evolution of histone genes].

From nucleotide sequences of more than 70 histones genes in 15 species of eucaryotes the probable frequency was determined for CpG----TpG + CpA substitutions, occurring as a result of deamination of 5-methylcytosine residues in DNA. It was found that histone genes differ in the character of CpG methylation with respect to the species studied and may be divided into three groups differing in the value of CpG suppression. In one of them, M-, CpG dinucleotides must have not been methylated throughout the existence of these genes; in another, M+, nearly every other CpG has undergone transition. In the third group, M +/-, no more than 20% of CpG have steadily undergone methylation (and mutation). The CpG deficiency in M+ and M +/- histone genes is in general proportional to the level of methylation of total DNA in different species. It has been noted that the genes of different core histones in the same organism are characterized, as a rule, by the same type of CpG methylation and belong to the same group. Genes H1 and H5 show a higher level of CpG suppression and thus have a higher degree of methylation than the genes of core histones from the same organism. The most conserved among the histone genes, those for H3 and H4 in particular, must have not been methylated in the majority of the species studied. The distribution of methylated and non-methylated spacers and coding sequences of histone genes of man, mouse, hen and yeast reveals a mosaic pattern. It has been found that 5'-flanked regions in most cases are methylated more than respective genes, while the G + C content in them is significantly lower, compared with the coding gene sequences. The absence of methylation in the 5'-regulatory regions does not appear to be mandatory for histone genes. It has been established that the genes of the same histones may differ in the level of methylation even in more or less closely related species. Group M- comprises genes of core histones of man, hen, sea urchin, Drosophila, Neurospora and wheat; group M +/- includes analogous genes of mouse, Xenopus, trout and sea urchins. The results obtained testify against the possible universal involvement of methylation in the regulation of histone gene expression.

Animals↗
PubMed2001

Molecular evolutionary analysis of a histone gene repeating unit from Drosophila simulans.

A repeating unit of the histone gene cluster from Drosophila simulans containing the H1, H2A, H2B and H4 genes (the H3 gene region has already been analyzed) was cloned and analyzed. A nucleotide sequence of about 4.6 kbp was determined to study the nucleotide divergence and molecular evolution of the histone gene cluster. Comparison of the structure and nucleotide sequence with those of Drosophila melanogaster showed that the four histone genes were located at identical positions and in the same directions. The proportion of different nucleotide sites was 6.3% in total. The amino acid sequence of H1 was divergent, with a 5.1% difference. However, no amino acid change has been observed for the other three histone proteins. Analysis of the GC contents and the base substitution patterns in the two lineages, D. melanogaster and D. simulans, with a common ancestor showed the following. 1) A strong negative correlation was found between the GC content and the nucleotide divergence in the whole repeating unit. 2) The mode of molecular evolution previously found for the H3 gene was also observed for the whole repeating unit of histone genes; the nucleotide substitutions were stationary in the 3' and spacer regions, and there was a directional change of the codon usage to the AT-rich codons. 3) No distinct difference in the mode or pattern of molecular evolution was detected for the histone gene repeating unit in the D. melanogaster and D. simulans lineages. These results suggest that selectional pressure for the coding regions of histones, which eliminate A and T, is less effective in the D. melanogaster and D. simulans lineages than in the other GC-rich species.

Amino Acid Sequence↗
PubMed1983

Codon-level analysis of histone primary sequence: evidence of a repeat tetrapeptide origin and later inclusion of transcribed sequence.

This work is directed to the question of protein sequence conservation. By reference to the genetic code the aminoacyl sequence of histones H2A, H4, H3, H2B and H1 (fragment) were rewritten as the codon sequences. The N-terminal regions were set aside on the grounds of different composition and sequence. The remainder of the molecule could be referred to simple repeat-tetrapeptide proteins by codon composition (high Gxy, low xGy content) and by sequence. Random segments of three to six residues occur characterized by composition and sequence as originating from the complimentary DNA strand, i.e. as codon "transcript". Ancestral features are probably best seen in H3, point mutations appear to be more extensive in H2B and H1. Segments in reverse order in H2A and in "transcript" in H4 distinguish these two from the other three histones. There is a tenuous possibility the N-terminals also originated as repeat-tetrapeptide now intensively modified. At codon-level the 50S ribosomal protein (L7/L12) of E. coli has features in common with histones (including a palindrome-containing N-terminal). It has the composition and sequence of a well-conserved tetrapeptide-repeat strand (statistical support). If interpretations made here are substantially correct, the 50S r-protein illustrates a significant stage in evolution of histone codon strands.

Amino Acid Sequence↗
PubMed2005

Sirtuins (histone deacetylases III) in the cellular response to DNA damage--facts and hypotheses.

Histone deacetylases (HDAC) are an important member of a group of enzymes that modify chromatin conformation. Homologues of the yeast gene SIR2 in mammalian cells code type III histone deacetylases (HDAC III, sirtuins), dependent on NAD(+) and inhibited by nicotinamide. In yeast cells, Sir2 participates in repression of transcriptional activity and in DNA double strand break repair. It is assumed that certain sirtuins may play a similar role in mammalian cells, by modifying chromatin structure and thus, altering the accessibility of the damaged sites for repair enzymes. A relation between poly(ADP-ribosylation) and sirtuin function in cells with damaged DNA has been also postulated. Interconnections between NAD(+) metabolism, poly(ADP-ribosylation), DNA repair and gene expression should allow to modulate the cellular response to agents that damage DNA. Preliminary results, reviewed in this paper indicate that such possibility exists. We propose a hypothetical mechanism of sirtuin participation in DSB repair. It is based on the assumption that activation of PARP at the sites of DNA strand breaks leads to a local increase in nicotinamide concentration. Nicotinamide then inhibits sirtuins exactly at the site of DNA strand break. At present, however, there are no data directly confirming the effect of sirtuin inhibition on DSB repair processes in mammalian cells. Nevertheless, a connection between the acetylation status of histones and repair of DNA breaks has recently been found, indicating that all HDAC classes may modulate DNA repair processes. In addition, sirtuins exert an anti-apoptotic action in various cell types. Hence, it is possible to sensitise cells to apoptosis-inducing agents by sirtuin inhibitors.

Animals↗
PubMed2006

Histone modifications: signalling receptors and potential elements of a heritable epigenetic code.

The genetic code epitomises simplicity, near universality and absolute predictive power. By contrast, epigenetic information, in the form of histone modifications, is characterised by complexity, diversity and an overall tendency to respond to changes in genomic function rather than to predict them. Perhaps the transient changes in histone modifications involved in intranuclear signalling and ongoing chromatin functions mask stable, predictive modifications that lie beneath. The current rapid progress in unravelling the diversity and complexity of epigenetic information might eventually reveal an underlying histone or epigenetic code. But whether it does or not, it will certainly provide unprecedented opportunities, both for understanding how the genome responds to environmental and metabolic change and for manipulating its activities for experimental and therapeutic benefit.

Chromatin↗
PubMed1978

Histone genes in macronuclear DNA of the ciliate Stylonychia mytilus.

DNA in the macronucleus of Stylonychia mytilus exists as discrete gene-sized fragments which are derived from micronuclear DNA through a series of well-defined developmental events. It has been proposed that each of the DNA fragments might represent a gene and its controlling elements. We have investigated this possibility using genes which code for the five histone proteins. Macronuclear DNA fragments were fractionated according to size by agarose gel electrophoresis, the fragments transferred to nitrocellulose filters using the technique of Southern, and the filter-bound DNA hybridized with labeled cloned histone genes of the sea urchin, Psammechinus miliaris. Results indicate, first, that sequences homologous to the five individual histone gene probes are present in discrete macronuclear fragments which appear as bands in the gel hybridization assay. Secondly, for each of the five individual histone gene probes the homologous DNA fragments are several in number, ranging in size in from 7.6 Kb (Kilo base pairs) to 0.73 Kb. For example, the largest of six detected fragments hybridizing to the H3 gene probe contains approximately 10 times the amount of DNA required to code for a Stylonychia H3 histone. The smallest detected fragment hybridizing to the H3 probe contains enought DNA to code for approximately two copies of the histone. Finally, in general, no two histone approximately two copies of the histone. Finally, in general, no two histone gene probes hybridized to the same macronuclear DNA fragment. This result indicates that genes coding for the five histones in Stylonychia are not located together on the same macronuclear DNA fragments and implies that the five functionally related genes would not be transcribed together as a polycistronic unit.

Animals↗
PubMed2005

A novel replication-independent histone H2a gene in mouse.

BACKGROUND: An uncharacterized histone H2a-coding transcript (E130307C13) has been cloned from a mouse full-length cDNA library. This transcript is encoded on chromosome 6, approximately 4 kb upstream of a histone H4 gene, Hist4h4. The proteins encoded by this transcript and the human H2afj mRNA isoform-2 have the highest amino acid similarity. In this paper, we characterize it from the expression pattern given by quantitative RT-PCR. RESULTS: Quantitative RT-PCR indicated that the gene that encodes E130307C13 (E130307C13) is regulated in a replication-independent manner, and therefore it is H2afj. Certainly, H2afj transcript lacks a stem-loop structure at the 3'-UTR but contains a poly (A) signal. In addition, its promoter region has a different structure from those of the replication-dependent histone H2a genes. CONCLUSION: The bioinformatics imply that E130307C13 is a replication-independent H2a gene. In addition, quantitative RT-PCR analysis shows that it is replication-independent. Thus, it is H2afj, a novel replication-independent H2a gene in mouse.

Animals↗
PubMed1989

Transcription from the intron-containing chicken histone H2A.F gene is not S-phase regulated.

The nucleotide sequence of an 8.2 kb BamHI fragment containing the entire chicken histone H2AF gene has been determined. Unlike the majority of histone genes, the coding region is interrupted by four intervening sequences. While sequencing the 8.2 kb BamHI fragment it was found that the promoter and first exon of an unidentified non-histone gene lies immediately downstream of the H2AF gene. Studies of H2AF gene transcription show that, unlike the major core and H1 histone genes, it is not coupled to DNA synthesis.

Amino Acid Sequence↗
PubMed1986

Sequences of four mouse histone H3 genes: implications for evolution of mouse histone genes.

The sequences of four histone H3 genes coding for the replication variant proteins H3.1 and H3.2 have been determined. Three of these genes, two coding for H3.1 proteins and one for an H3.2 protein, are located on chromosome 13 and expressed at low levels. The fourth gene, encoding an H3.2 protein, is located on chromosome 3 and expressed at a high level. The coding regions of the three genes on chromosome 13 are more similar to each other than to the H3 gene on chromosome 3, and equally divergent from it, suggesting that either gene duplication or gene conversion has occurred since the genes were dispersed onto two chromosomes. A 14-base sequence including the CCAAT sequence and located 5' to the genes on chromosome 13 has been conserved. The histone H3 gene on chromosome 3 has multiple potential binding sites for the Sp1 transcription factor. The coding regions show greater than 95% conservation among the four genes. This is due to the strict pattern of codon usage and the presence of two long (greater than 60 base) regions of completely conserved nucleic acid sequence. These conserved regions in the coding sequence may have an important functional role at the mRNA or DNA level.

Amino Acid Sequence↗
PubMed1996

3' Processing and termination of mouse histone transcripts synthesized in vitro by RNA polymerase II.

The highly expressed mouse histone H2a-614 gene is located 800 nt 5' of the histone H3-614 gene. There is a 140 nt sequence located 500 nt from the end of the H2-614 mRNA which has been defined as a transcription termination site for RNA polymerase II. We established an in vitro transcription system in which both 3' end processing and transcription termination occur. A template containing the adenovirus major late promoter, a portion of the histone H2a-614 coding region, its 3' processing signal, followed by the transcription termination site was transcribed in a nuclear extract prepared from mouse myeloma cells. Some of the transcripts synthesized in the extract were cleaved at the histone processing site in a reaction which was dependent both on the hairpin binding factor and the U7 snRNP. The efficiency of histone 3' end formation was similar both on synthetic transcripts and transcripts synthesized by RNA polymerase II. Defined transcripts, which were not processed and which mapped to the transcription termination site, were released from the template, suggesting that they were formed by transcription termination. Termination in vitro was dependent on a functional histone processing signal.

Animals↗