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PubMed1994

Molecular characterization and transcription of the histone H2B gene from the protozoan parasite Trypanosoma cruzi.

The structure, genomic organization and transcription of the gene encoding histone H2B in the protozoan parasite Trypanosoma cruzi have been studied. This gene consists of a 746-nucleotide unit, tandemly repeated at least 18 times in each of two clusters. DNA probes corresponding to histones H2B and H3 hybridized to different chromosomes revealing that the genes coding for these two histones are not physically linked in the genome of T. cruzi. The primary transcription product of the H2B gene is processed by trans-splicing and polyadenylation. Inhibition of DNA synthesis with aphidicolin resulted in the reduction of histone H2B mRNA to undetectable levels in about two hours, suggesting that its abundance is regulated throughout the cell cycle as it occurs in other eukaryotes. In addition, a concomitant inhibition of translation by cycloheximide reverted this effect indicating that de novo protein synthesis is required for RNA instability. Histone mRNA abundance was dependent on the life-cycle stage of T. cruzi: abundant in amastigotes and epimastigotes, the dividing forms in the host cell and the insect vector, respectively, while undetected in trypomastigotes, the parasite's non-dividing life stage.

Amino Acid Sequence↗

PubMed2000

Roles of transcription factor Mot3 and chromatin in repression of the hypoxic gene ANB1 in yeast.

The hypoxic genes of Saccharomyces cerevisiae are repressed by a complex consisting of the aerobically expressed, sequence-specific DNA-binding protein Rox1 and the Tup1-Ssn6 general repressors. The regulatory region of one well-studied hypoxic gene, ANB1, is comprised of two operators, OpA and OpB, each of which has two strong Rox1 binding sites, yet OpA represses transcription almost 10 times more effectively than OpB. We show here that this difference is due to the presence of a Mot3 binding site in OpA. Mutations in this site reduced OpA repression to OpB levels, and the addition of a Mot3 binding site to OpB enhanced repression. Deletion of the mot3 gene also resulted in reduced repression of ANB1. Repression of two other hypoxic genes in which Mot3 sites were associated with Rox1 sites was reduced in the deletion strain, but other hypoxic genes were unaffected. In addition, the mot3Delta mutation caused a partial derepression of the Mig1-Tup1-Ssn6-repressed SUC2 gene, but not the alpha2-Mcm1-Tup1-Ssn6-repressed STE2 gene. The Mot3 protein was demonstrated to bind to the ANB1 OpA in vitro. Competition experiments indicated that there was no interaction between Rox1 and Mot3, indicating that Mot3 functions either in Tup1-Ssn6 recruitment or directly in repression. A great deal of evidence has accumulated suggesting that the Tup1-Ssn6 complex represses transcription through both nucleosome positioning and a direct interaction with the basal transcriptional machinery. We demonstrate here that under repressed conditions a nucleosome is positioned over the TATA box in the wild-type ANB1 promoter. This nucleosome was absent in cells carrying a rox1, tup1, or mot3 deletion, all of which cause some degree of derepression. Interestingly, however, this positioned nucleosome was also lost in a cell carrying a deletion of the N-terminal coding region of histone H4, yet ANB1 expression remained fully repressed. A similar deletion in the gene for histone H3, which had no effect on repression, had only a minor effect on the positioned nucleosome. These results indicate that the nucleosome phasing on the ANB1 promoter caused by the Rox1-Mot3-Tup1-Ssn6 complex is either completely redundant with a chromatin-independent repression mechanism or, less likely, plays no role in repression at all.

Aerobiosis↗

PubMed1987

Mouse histone H2A and H2B genes: four functional genes and a pseudogene undergoing gene conversion with a closely linked functional gene.

The sequence of five mouse histone genes, two H2a and three H2b genes on chromosome 13 has been determined. The three H2b genes all code for different proteins, each differing in two amino acids from the others. The H2b specific elements present 5' to H2b genes from other species are present in all three mouse H2b genes. All three H2b genes are expressed in the same relative amounts in three different mouse cell lines and fetal mice. The H2b gene with the H2b specific sequence closest to the TATAA sequence is expressed in the highest amount. One of the H2a genes lacks the first 9 amino acids, the promoter region, the last 3 amino acids and contains an altered 3' end sequence. Despite these multiple defects, there is only one nucleotide change between the two H2a genes from codon 9 to 126. This indicates that a recent gene conversion has occurred between these two genes. The similarity of the nucleotide sequences in the coding regions of mouse histone genes is probably due to gene conversion events targeted precisely at the coding region.

Animals↗

PubMed1988

Persistence of a micrococcal nuclease sensitive region spanning the promoter-coding region junction of a cell cycle regulated human H4 histone gene throughout the cell cycle.

We have examined the chromatin structure of the cell cycle regulated human H4 histone gene FO108A at various times during the cell cycle, by treating nuclei isolated from synchronized HeLa S3 cells with micrococcal nuclease. Purified DNA was fractionated electrophoretically, transferred to nitrocellulose, and hybridized to small (150-250 nucleotides) radiolabeled probes from various portions of the promoter and coding regions of the gene. Our results indicate the existence of a micrococcal nuclease sensitive region located between positions -60 and +90 base pairs (bp) from the start codon of the gene, which includes the TATA box. This nuclease-sensitive region persists at all the cell cycle times analyzed. Hybridization with a 250-bp probe containing only coding region sequences reveals a disrupted nucleosomal ladder during early S phase, when this H4 histone gene replicates and exhibits an enhanced level of transcription. By mid-S phase, the regular nucleosomal structure of the coding region is restored and persists during subsequent phases of the cell cycle. The disruption of a normal nucleosomal organization in the promoter and mRNA coding regions of this H4 histone gene is also supported by the sensitivity of these sequences to S1 nuclease.

Chromatin↗

PubMed1988

Cell-cycle regulation as a mechanism for targeting proteins to specific DNA sequences in Tetrahymena thermophila.

Transcriptionally active macronuclei and transcriptionally inert micronuclei of the ciliated protozoan Tetrahymena thermophila contain similar DNA sequences but have very different histones associated with the linker regions of chromatin. In situ hybridization showed that a gene coding for micronuclear linker histone is expressed only in association with micronuclear DNA replication, whereas the gene for macronuclear H1 histone is expressed during macronuclear (but not during micronuclear) S phase. These results indicate that cell-cycle regulation plays an important role in directing proteins to the appropriate nucleus in Tetrahymena and that the replication-expression model [Gottesfeld, J. & Bloomer, L. S. (1982) Cell 28, 781-791; Wormington, W. M., Schlissel, M. & Brown, D. D. (1983) Cold Spring Harbor Symp. Quant. Biol. 47, 879-884] for establishing appropriate transcriptionally active or repressed chromatin complexes during DNA replication is generally applicable.

Animals↗

PubMed1997

Positional preferences of polypurine/polypyrimidine tracts in Saccharomyces cerevisiae genome: implications for cis regulation of gene expression.

The complete genome of the baker's yeast S. cerevisiae was analyzed for the presence of polypurine/polypyrimidine (poly[pu/py]) repeats and their occurrences were classified on the basis of their location within and outside open reading frames (ORFs). The analysis reveals that such sequence motifs are present abundantly both in coding as well as noncoding regions. Clear positional preferences are seen when these tracts occur in noncoding regions. These motifs appear to occur predominantly at a unit nucleosomal length both upstream and downstream of ORFs. Moreover, there is a biased distribution of polypurines in the coding strands when these motifs occur within open reading frames. The significance of the biased distribution is discussed with reference to the occurrence of these motifs in other known mRNA sequences and expressed sequence tags. A model for cis regulation of gene expression is proposed based on the ability of these motifs to form an intermolecular triple helix structure when present within the coding region and/or to modulate nucleosome positioning via enhanced histone affinity when present outside coding regions.

Chromosome Mapping↗

PubMed1997

A conserved element in the protein-coding sequence is required for normal expression of replication-dependent histone genes in developing Xenopus embryos.

Replication-dependent histone genes in the mouse and Xenopus share a common regulatory element within the protein-encoding sequence called the CRAS alpha element (coding region activating sequence alpha) which has been shown to mediate normal expression in vivo and to interact with nuclear factors in vitro in a cell cycle-dependent manner. Thus far, the alpha element has only been studied in rodent cells in culture, and its effect on histone gene expression during development has not been determined. Here we examine the role of the alpha element in histone gene expression during Xenopus development which features a switch in histone gene expression from a replication-independent mode in oocytes to a replication-dependent mode in embryos after midblastula stage. In vivo expression experiments involving wild-type or alpha-mutant mouse H3.2 genes show that mutation of the CRAS alpha element results in a fourfold decline of expression in embryos, but does not affect expression in oocytes. Two distinct alpha sequence-specific binding activities were detected in both oocyte and embryonic extracts. A slowly migrating DNA-binding complex was present at relatively constant levels throughout development from the earliest stages of oogenesis through larval stages. In contrast, levels of a rapidly migrating complex were high in stage I and II oocytes, declined in stage II-VI oocytes, remained low in unfertilized eggs and cleavage stage embryos, and rose dramatically after the midblastula transition. The molecular masses of the factors forming the slow and rapidly migrating complexes were estimated to be approximately 110 and 85 kDa, respectively. DNA-binding activity of the 85 kDa alpha-binding factor was affected by phosphorylation, binding with higher affinity in the dephosphorylated state. The abrupt increase in DNA-binding activity of the 85-kDa alpha-binding factor at late blastula coincides with the switch to the replication-dependent mode of histone gene expression. We propose that the conserved alpha element present in the coding sequence of mouse and Xenopus core histone genes is required for normal replication-dependent histone expression in the developing Xenopus embryo.

Animals↗

PubMed1983

Histone mRNA concentrations are regulated at the level of transcription and mRNA degradation.

The levels of histone mRNA are rapidly reduced after treatment of cultured cells with hydroxyurea or cytosine arabinonucleoside. The histone mRNA for the replicative histone variants is destroyed rapidly, with a half-life of 10-15 min. The levels of mRNA coding for the replacement histone variant H3.3 were unchanged after treatment with DNA synthesis inhibitors. In addition to the rapid destruction of histone mRNA, there was a reduction to 1/5th in the rate of transcription of the histone genes. Lymphoma cells (S49) arrested in G1 by cyclic AMP produce and contain significant levels of histone mRNA. Hydroxyurea reduces the rate of transcription and the levels of histone mRNA in the G1-arrested cells.

Animals↗

PubMed1993

Selective recruitment of masked maternal mRNA from messenger ribonucleoprotein particles containing FRGY2 (mRNP4).

In Xenopus, the germ cell-specific Y-box (CTGATTGGCCAA) factor, FRGY2, facilitates in vitro transcription in egg extracts from oocyte-selective promoters containing a Y-box. This same factor is a major component of the messenger ribonucleoprotein (mRNP) storage particles of the oocyte. These particles store maternal mRNAs and inhibit their translation. FRGY2 is identical to mRNP4 and homologous to mRNP3, two previously described oocyte-specific mRNP proteins. We demonstrate that FRGY2 associates with a broad spectrum of mRNAs exhibiting no apparent sequence specificity. These interactions suggest that FRGY2 has a general role in packaging mRNA analogous to that of histone with DNA. All mRNAs examined that accumulate in oocytes appear within these mRNP storage particles, including messages coding for proteins such as FRGY2 and TFIIIA, which are translated in the oocyte. Moreover, we show that mRNAs that are translationally repressed in oocytes, such as messages coding for the proteins histone H1 and FRGY1, accumulate only within the particles. These mRNAs are subsequently recruited from the particles to the ribosomes and utilized for translation during embryogenesis prior to transcriptional activation of the zygotic genome. We propose that the assembly of mRNP storage particles represents a default state and that translational regulation is achieved via specific recruitment of the messages from the mRNP fraction to the ribosomes.

Animals↗

PubMed1996

cDNA cloning and characterization of buforin I, an antimicrobial peptide: a cleavage product of histone H2A.

A cDNA containing coding information for buforin I, the toad stomach antimicrobial peptide, was identified by PCR. The cloned cDNA encoded a protein of 129 amino acids whose 39-amino-acid N-terminus was identical to buforin I. Nucleotide sequence analysis of the cloned cDNA revealed that it had over 90% amino acid homology with histone H2A, the replication-dependent protein. Both Northern and Southern blot analysis of the toad genome suggested that histone H2A and buforin I were encoded by the same gene. A specific protease responsible for the generation of buforin I from histone H2A was found to be present in the crude extracts of the toad stomach. These results suggest that there exists a specific regulation mechanism which converts the toad histone H2A to the antimicrobial peptide buforin I.

Amino Acid Sequence↗

PubMed1978

Genes and spacers of cloned sea urchin histone DNA analyzed by sequencing.

A cloned histone gene cluster of the highly reiterated type from the sea urchin Psammechinus miliaris was analyzed by DNA sequencing. More than half of the 6 kb repeat was sequenced, including coding regions of all five histones, some prelude and trailing sequences lying adjacent to the structural gense, and segments of the AT-rich spacer DNA. The gene cluster does not code for gonad-specific histone variants but may instead be active in early sea urchin development, as indicated by comparison to reference histones. The encoded histones seem not to be derived from longer precursor proteins, not is there any evidence for insert sequences within the coding regions. Sequence similarities exist among the putative ribosome-binding sites adjacent to the initiator codons of individual genes. The AT-rich spacer segments between the genes differ from each other, are made up from relatively simple nucleotide arrangements, but are not repetitious, and apparently do not code for additional large proteins.

Animals↗

PubMed1979

Isolation of a genomal clone containing chicken histone genes.

We have used enriched chicken histone cDNA to select genomal clones from a chicken library. Because the cDNA probe also contained other sequences, a further screening of positive plagues with negative probes eliminated most non-histone gene clones. One 'positively-selected' genomal clone, lambda CH-01, hybridised with cloned sea-urchin histone genes and also detected histone genes in EcoRI-digested genomal sea-urchin DNA. Limited DNA sequencing of HaeIII fragments identified two sequences within the coding region of chicken histone H2A. A third fragment predicted an amino acid sequence with strong homology to an H1 histone sequence.

Amino Acid Sequence↗

PubMed1990

Coding and noncoding sequences at the 3' end of yeast histone H2B mRNA confer cell cycle regulation.

Yeast (Saccharomyces cerevisiae) histone mRNA synthesis is tightly regulated to the S phase of the cell division cycle as a result of both transcriptional and posttranscriptional regulation. We focused on the role of posttranscriptional control in histone H2B1 gene (HTB1) regulation and studied a portion of the HTB1 message required for cell-cycle-specific accumulation. The 3' end of the HTB1 gene containing a 17-amino-acid coding sequence and entire noncoding sequence was fused to the bacterial neomycin phosphotransferase II gene (neo) under control of the GAL1 promoter. The expression of the endogenous and chimeric HTB1 genes was analyzed during the yeast cell cycle. As yeast cells entered a synchronous cell cycle following release from alpha-factor arrest, the level of GAL1-promoter-controlled neo-HTB1 message increased approximately 12-fold during S phase and dropped to basal level when the cells left S phase. This indicates that the 3' end of the HTB1 mRNA is capable of conferring cycle-specific regulation on a heterologous message. Deletion analysis of the 3' end showed that the signal for cell cycle control of HTB1 mRNA includes contiguous coding and noncoding sequences surrounding the stop codon. This differs from the situation in mammalian cells, whose posttranscriptional regulation of histone genes is mediated through a short sequence containing a stem-loop structure near the very terminus of the untranslated 3' end.

Base Sequence↗

PubMed1998

Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones.

We cloned a cDNA coding for a novel serine/threonine kinase, Dlk, a protein of 448 amino acids with a predicted molecular weight of 51.3 kDa. The kinase domain shows 81% amino acid sequence identity to the recently identified DAP kinase (death associated protein kinase) (Deiss et al., Genes & Dev., 9, 15-30, 1995), therefore, the new kinase was called Dlk, for DAP like kinase. Northern analyses revealed a single mRNA species of 1.7 kb which was ubiquitously expressed. However, expression levels varied considerably in different cell lines and tissues. Moreover, expression was downregulated upon UV irradiation. Dlk exhibited autophosphorylation activity, predominantly towards threonine residues and phosphorylated the regulatory subunit of myosin light chain, but in this case exclusively at serine residues. Dlk seems to be tightly associated with insoluble nuclear structures, presumably chromatin, since it was resistant to various rigorous extraction procedures but it was partially released upon DNase I digestion of nuclei. Consistent with this, purified Dlk phosphorylated core histones H3, H2A and H4 as exogenous substrates and endogenous histone H3 in kinase assays with nuclear extracts. Expression as GFP-fusion protein revealed a diffuse as well as a speckled nuclear staining suggesting an association with replication or transcription centers.

Amino Acid Sequence↗

PubMed2000

Deletion of the unique gene encoding a typical histone H1 has no apparent phenotype in Aspergillus nidulans.

We have cloned the H1 histone gene (hhoA) of Aspergillus nidulans. This single-copy gene codes for a typical linker histone with one central globular domain. The open reading frame is interrupted by six introns. The position of the first intron is identical to that of introns found in some plant histones. An H1-GFP fusion shows exclusive nuclear localization, whereas chromosomal localization can be observed during condensation at mitosis. Surprisingly, the deletion of hhoA results in no obvious phenotype. The nucleosomal repeat length and susceptibility to micrococcal nuclease digestion of A. nidulans chromatin are unchanged in the deleted strain. The nucleosomal organization of a number of promoters, including in particular the strictly regulated niiA-niaD bidirectional promoter is not affected.

Amino Acid Sequence↗

PubMed1990

A cytotoxic monoclonal anti-leukemia antibody binds to histone H1.

Monoclonal antibody (MAb) AP64 is a mouse IgM MAb raised against human acute non-lymphocytic leukemia (ANLL) cells. It has been shown to bind to a wide variety of cell lines and is capable of initiating complement (C) dependent cytotoxicity. Other studies indicated that MAb AP64 can effect long term cure in a leukemia minimal residual disease model. By using various techniques we have determined the identity of a protein which is bound by this MAb. Immunofluorescent studies have shown that MAb AP64 stains the nuclei of fixed cells as well as metaphase chromosomes, indicating that this MAb binds to a component of chromatin. Biochemical characterization revealed that MAb AP64 western blots a 31 and 32 kilodalton doublet from NP-40 extracts from both rat and human leukemia cells. The mobility of this doublet is identical under reducing and non-reducing conditions. Further studies have shown that the bands detected by western blot analysis using MAb AP64 as a probe have a similar migration to those of bovine histone H1. Also, 1 nanogram of bovine histone H1 can be detected by MAb AP64 when spotted onto nitrocellulose. These data demonstrate that MAb AP64 binds to a conserved epitope present on molecules coded for by the histone H1 gene family.

Antibodies, Monoclonal↗

PubMed1999

Several highly divergent histone H3 genes are present in the hypotrichous ciliate Stylonychia lemnae.

In the protozoan Stylonychia lemnae 10 different histone H3 genes were discovered by polymerase chain reaction (PCR) amplification and sequence analysis. One of them is interrupted by a short intron sequence. These genes code for nine divergent histone H3 proteins. The genetic distances between some of these variants are very high. Most of the substitutions, as well as insertions/deletions, were found in the amino-terminal region. One variant shows an extremely elongated and altered N-terminus, which did not allow an unambiguous alignment with other histone H3 variants in this region. Hybridization experiments using the different H3 genes as probes indicate that even more histone H3 variants must exist in this species.

Amino Acid Sequence↗

PubMed1985

An unusual genetic code in nuclear genes of Tetrahymena.

We have cloned and partially sequenced two histone H3 genes of Tetrahymena thermophila. The DNA sequences strongly suggest that both genes are active in the vegetatively growing cell. Comparison of the derived amino acid sequences of these two genes with the actual sequence of Tetrahymena histone H3 results in the surprising conclusion that TAA codes for glutamine. This represents the first demonstration of a coding function for this termination codon of the "universal" code. This observation has important implications for the evolution of ciliates and of the genetic code.

Amino Acid Sequence↗