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PubMed1985

Changes in the levels of three different classes of histone mRNA during murine erythroleukemia cell differentiation.

We used a gene-specific S1 nuclease assay to study the changes in steady-state mRNA levels of several core histone variants during the differentiation of murine erythroleukemia cells. These studies allowed us to distinguish three distinct expression classes of histone genes. The expression of the major replication-dependent class of histone genes was tightly linked to DNA synthesis. The concentrations of these transcripts decreased rapidly as cell division slowed during the process of differentiation. In contrast, the replication-independent H3.3 transcript levels were constitutively maintained throughout differentiation and were unaffected by inhibitors of DNA or protein synthesis. We also identified among the cloned histone genes used as probes a third expression class, the partially replication-dependent variants. Expression of these transcripts became transiently uncoupled from the reduced rate of DNA synthesis accompanying the early stages of differentiation. We show that their synthesis is sensitive to the DNA synthesis inhibitor hydroxyurea but that selective uncoupling from DNA synthesis of these histone mRNAs occurs at a specific stage of differentiation. We present several hypotheses to explain how this might be accomplished. The expression characteristics of the mRNAs studied coincided with those of the proteins for which they code, indicating that changes in the relative levels of the different variants is mediated at least in part by changes in mRNA levels.

Animals↗
PubMed2005

Replication-independent core histone dynamics at transcriptionally active loci in vivo.

We used a novel labeling technique in the naturally synchronous organism Physarum polycephalum to examine the fate of core histones in G2 phase. We find rapid exchange of H2A/H2B dimers with free pools that is greatly diminished by treatment of the cells with alpha-amanitin. This exchange is enhanced in pol II-coding sequences compared with extragenic regions or inactive loci. In contrast, H3/H4 tetramers exhibit far lower levels of exchange in the pol II-transcribed genes tested, suggesting that tetramer exchange occurs via a distinct mechanism. However, we find that transcribed regions of the ribosomal RNA gene loci exhibit rapid exchange of H3/H4 tetramers. Thus, our data show that the majority of the pol II transcription-dependent histone exchange is due to elongation in vivo rather than promoter remodeling or other pol II-dependent alterations in promoter structure and, in contrast to pol I, pol II transcription through nucleosomes in vivo causes facile exchange of both H2A/H2B dimers while allowing conservation of epigenetic "marks" and other post-translational modifications on H3 and H4.

Amanitins↗
PubMed1993

A wheat histone H3 promoter confers cell division-dependent and -independent expression of the gus A gene in transgenic rice plants.

To investigate developmental regulation of wheat histone H3 gene expression, the H3 promoter, which has its upstream sequence to -1711 (relative to the cap site as +1), was fused to the coding region of the gus A gene (-1711H3/GUS) and introduced into a monocot plant, rice. Detailed histochemical analysis revealed two distinct types of GUS expression in transgenic rice plants; one is cell division-dependent found in the apical meristem of shoots and roots and in young leaves, and another is cell division-independent detected in flower tissues including the anther wall and the pistil. In this study, replication-dependent expression occurring in non-dividing cells which undergo endoreduplication could not be discriminated from strict replication-independent expression. The observed expression pattern in different parts of roots suggested that the level of the H3/GUS gene expression is well correlated with activity of cell division in roots. To identify 5' sequences of the H3 promoter necessary for an accurate regulation of the GUS expression, two constructs containing truncated promoters, -908H3/GUS and -185H3/GUS, were analyzed in transiently expressed protoplasts, stably transformed calli and transgenic plants. The results indicated that the region from -909 to -1711 contains the positive cis-acting element(s) and that the proximal promoter region (up to -185) containing the conserved hexamer, octamer and nonamer motifs is sufficient to direct both cell division-dependent and -independent expression. The use of the meristem of roots regenerated from transformed calli for the analysis of cell division-dependent expression of plant genes is discussed.

Base Sequence↗
PubMed1988

Sequence of cDNAs for mammalian H2A.Z, an evolutionarily diverged but highly conserved basal histone H2A isoprotein species.

The nucleotide sequences of cDNAs for the evolutionarily diverged but highly conserved basal H2A isoprotein, H2A.Z, have been determined for the rat, cow, and human. As a basal histone, H2A.Z is synthesized throughout the cell cycle at a constant rate, unlinked to DNA replication, and at a much lower rate in quiescent cells. Each of the cDNA isolates encodes the entire H2A.Z polypeptide. The human isolate is about 1.0 kilobases long. It contains a coding region of 387 nucleotides flanked by 106 nucleotides of 5'UTR and 376 nucleotides of 3'UTR, which contains a polyadenylation signal followed by a poly A tail. The bovine and rat cDNAs have 97 and 94% nucleotide positional identity to the human cDNA in the coding region and 98% in the proximal 376 nucleotides of the 3'UTR which includes the polyadenylation signal. A potential stem-forming sequence imbedded in a direct repeat is found centered at 261 nucleotides into the 3'UTR. Each of the cDNA clones could be transcribed and translated in vitro to yield H2A.Z protein. The mammalian H2A.Z cDNA coding sequences are approximately 80% similar to those in chicken and 75% to those in sea urchin.

Amino Acid Sequence↗
PubMed1986

Nucleotide sequence of a cDNA clone encoding Scylliorhinus caniculus protamine Z2.

A cDNA library was constructed from a protamine-enriched fraction of dogfish (Scylliorhinus caniculus) mRNA. The nucleotide sequence of a 440-bp insert was determined, and its produced protein sequence confirmed its identification as a cysteine-rich protamine Z2 [Martinage, A., Gusse, M., Belaiche, D., Sautiere, P. and Chevaillier, P. (1985) Biochim. Biophys. Acta 831, 172-178]. The frequency of utilization of the different triplets coding for arginine, which represents 30-70% of the total amino acid residues for trout, mouse and dogfish protamines, is discussed. An alternative repetitive sequence of CGC-AGG was found in the N terminus of the protein. Analysis of the 3' flanking region after the mRNA-terminating TAA codon identified an inverted repeat sequence and an ACCA sequence, which may be possible vestiges of a histone-like termination signal.

Animals↗
PubMed2000

Histone acetylation modifiers in the pathogenesis of malignant disease.

Chromatin structure is gaining increasing attention as a potential target in the treatment of cancer. Relaxation of the chromatin fiber facilitates transcription and is regulated by two competing enzymatic activities, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which modify the acetylation state of histone proteins and other promoter-bound transcription factors. While HATs, which are frequently part of multisubunit coactivator complexes, lead to the relaxation of chromatin structure and transcriptional activation, HDACs tend to associate with multisubunit core-pressor complexes, which result in chromatin condensation and transcriptional repression of specific target genes. HATs and HDACs are known to be involved both in the pathogenesis as well as in the suppression of cancer. Some of the genes encoding these enzymes have been shown to be rearranged in the context of chromosomal translocations in human acute leukemias and solid tumors, where fusions of regulatory and coding regions of a variety of transcription factor genes result in completely new gene products that may interfere with regulatory cascades controlling cell growth and differentiation. On the other hand, some histone acetylation-modifying enzymes have been located within chromosomal regions that are particularly prone to chromosomal breaks. In these cases gains and losses of chromosomal material may affect the availability of functionally active HATs and HDACs, which in turn disturbs the tightly controlled equilibrium of histone acetylation. We review herein the recent achievements, which further help to elucidate the biological role of histone acetylation modifying enzymes and their potential impact on our current understanding of the molecular changes involved in the development of solid tumors and leukemias.

Acetylation↗
PubMed2006

Hairpin RNA: a secondary structure of primary importance.

An RNA hairpin is an essential secondary structure of RNA. It can guide RNA folding, determine interactions in a ribozyme, protect messenger RNA (mRNA) from degradation, serve as a recognition motif for RNA binding proteins or act as a substrate for enzymatic reactions. In this review, we have focused on cis-acting RNA hairpins in metazoa, which regulate histone gene expression, mRNA localization and translation. We also review evolution, mechanism of action and experimental use of trans-acting microRNAs, which are coded by short RNA hairpins. Finally, we discuss the existence and effects of long RNA hairpin in animals. We show that several proteins previously recognized to play a role in a specific RNA stem-loop function in cis were also linked to RNA silencing pathways where a different type of hairpin acts in trans. Such overlaps indicate that the relationship between certain mechanisms that recognize different types of RNA hairpins is closer than previously thought.

Animals↗
PubMed1974

Partial purification of the template-active fraction of chromatin: a preliminary report.

A fraction of rat-liver chromatin that is transcriptionally active in vivo has been purified 6- to 7-fold over whole chromatin. This was accomplished by selectively shearing chromatin with DNase II followed by fractionating the released portion on the basis of its solubility properties in 2 mM MgCl(2). The resulting soluble material comprises 11% of the total chromatin DNA and is impoverished in histone and enriched in nonhistone protein. Compared with unsheared chromatin, this minor fraction exhibits marked differences in chromosomal protein species. DNA renaturation studies indicate that this fraction is composed of a specific subset of whole genomal DNA sequences. Furthermore, DNA.RNA hybridization experiments suggest that almost 60% of the nonrepetitious DNA sequences of this minor fraction could code for cellular RNA.

Animals↗
PubMed2002

Phosphorylation of histone h3 at serine 10 cannot account directly for the detachment of human heterochromatin protein 1gamma from mitotic chromosomes in plant cells.

Heterochromatin protein 1 (HP1) controls heterochromatin formation in animal cells, at least partly through interaction with lysine 9 (Lys-9)-methylated histone H3. We aimed to determine whether a structurally conserved human HP1 protein exhibits conserved heterochromatin localization in plant cells and studied its relation to modified histone H3. We generated transgenic tobacco plants and cycling cells expressing the human HP1gamma fused to green fluorescent protein (GFP) and followed its association with chromatin. Plants expressing GFP-HP1gamma showed no phenotypic perturbations. We found that GFP-HP1gamma is preferentially associated with the transcriptionally "inactive" heterochromatin fraction, a fraction enriched in Lys-9-methylated histone H3. During mitosis GFP-HP1gamma is detached from chromosomes concomitantly with phosphorylation of histone H3 at serine 10 and reassembles as cells exit mitosis. However, this phosphorylation cannot directly account for the dissociation of GFP-HP1gamma from mitotic chromosomes inasmuch as phosphorylation does not interfere with binding to HP1gamma. It is, therefore, possible that phosphorylation at serine 10 creates a "code" that is read by as yet an unknown factor(s), eventually leading to detachment of GFP-HP1gamma from mitotic chromosomes. Together, our results suggest that chromatin organization in plants and animals is conserved, being controlled at least partly by the association of HP1 proteins with methylated histone H3.

Cell Nucleus↗
PubMed2000

The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations.

We identified antibacterial components in human T and natural killer (NK) cells by using freshly isolated lymphocytes enriched for T and NK cells as starting material. After growing these lymphocytes for 5 days in the presence of interleukin (IL)-2, we isolated and characterized several antibacterial peptides/proteins from the supernatant-alpha-defensins (HNP 1-3), LL-37, lysozyme, and a fragment of histone H2B-although other active components were also present. We then used reverse transcriptase-polymerase chain reaction to search for expression of the gene coding for LL-37 in several B-cell lines, gammadelta T-cell lines, NK clones, and one monocytic cell line, with positive results, but found no expression in several alphabeta T-cell lines. The alpha-defensins (HNP 1-3) were also found to be expressed in several of these cell lines. To confirm the presence of these antibacterial peptides in lymphocytes, we localized them to NK, gammadelta T cells, B cells, and monocytes/macrophages by using double-staining immunohistochemical analysis of freshly isolated lymphocytes. We also found that primary cultures of lymphocytes transcribe and secrete LL-37 and that these processes are affected by IL-6 and interferon-gamma. In addition, we demonstrated that LL-37 has chemotactic activity for polymorphonuclear leukocytes and CD4 T lymphocytes, whereas others have shown chemotactic activity for human alpha-defensins (HNP 1-2). These findings suggest that microbicidal peptides are effector molecules of lymphocytes and that antibacterial activity previously shown to be derived from T and NK cells may be partly mediated by the antibacterial peptides LL-37 and HNP 1-3.

Anti-Bacterial Agents↗
PubMed2005

Histone H3 lysine 4 mono-methylation does not require ubiquitination of histone H2B.

The yeast Set1-complex catalyzes histone H3 lysine 4 (H3K4) methylation. Using N-terminal Edman sequencing, we determined that 50% of H3K4 is methylated and consists of roughly equal amounts of mono, di and tri-methylated H3K4. We further show that loss of either Paf1 of the Paf1 elongation complex, or ubiquitination of histone H2B, has only a modest effect on bulk histone mono-methylation at H3K4. Despite the fact that Set1 recruitment decreases in paf1delta cells, loss of Paf1 results in an increase of H3K4 mono-methylation at the 5' coding region of active genes, suggesting a Paf1-independent targeting of Set1. In contrast to Paf1 inactivation, deleting RTF1 affects H3K4 mono-methylation at the 3' coding region of active genes and results in a decrease of global H3K4 mono-methylation. Our results indicate that the requirements for mono-methylation are distinct from those for H3K4 di and tri-methylation, and point to differences among members of the Paf1 complex in the regulation of H3K4 methylation.

Histones↗
PubMed2000

Unexpectedly high variability of the histone H4 gene in Leishmania.

The sequence of the cDNA of the histone H4 gene of Leishmania tarentolae is reported herein. The predicted 100-amino-acid-long protein has the highest degree of identity with the histone H4 gene of L. infantum and shares with it a 5' region that shows a very low degree of identity with the corresponding region of histone H4 genes from other organisms. However, between these two genes is a 7.7% nucleotide difference that results in seven different amino acids, located in the 5', central, and 3' regions of the coding sequence. Such a divergence in the H4 gene, which is considered to be one of the most highly conserved genes, between closely related members of the genus Leishmania is unexpected and may reflect some unusual features of these important proteins in kinetoplastid flagellates.

Amino Acid Sequence↗
PubMed1981

Periodic correlations in DNA sequences and evidence suggesting their evolutionary origin in a comma-less genetic code.

Strong rhythms with a period of three bases have been seen while correlating the relative positions of purines and pyrimidines and of the four individual bases in the complete DNA sequence of the viruses phi X174, G4 and fd. Generally weaker variations of the same type have been found in the DNA virus SV40, the plasmid pBR322, the RNA virus MS2, and elsewhere in procaryotes and eucaryotes (e.g. in a ribosomal protein gene cluster of E. coli and the sea urchin histone genes). From the interrelation of four-base with purine-pyrimidine rhythms it seems that the purine-pyrimidine relationships have a basic significance. An explanation is proposed in terms of the former use of a comma-less genetic code (i.e. readable only in one frame) of the general form RNY (R = purine, Y = pyrimidine and N = purine or pyrimidine). In spite of subsequent mutation, there appears to be still enough of the primitive messages remaining to produce these periodic variations with their characteristic properties in phase and amplitude. Particularly good evidence for this hypothesis is provided by the fact that the phases for the stronger rhythms are the same in all the genomes tested and can be successfully predicted by a simple consideration of the original RNY pattern. With regard to amplitude it can be similarly foreseen which variations will be more clearly marked than others. The observed behaviour of the amplitude as the separation between correlated bases increases is also explained by the insertions, deletions and point mutations which have occurred. Additionally it is possible to account for some notable features of the non-random use of codons for the same amino acid by this theory.

Base Sequence↗
PubMed1999

Co-localization of HP1 and TP1 transcripts in human spermatids by double electron microscopy in situ hybridization.

Nuclear changes in the basic nucleoprotein complement occur during spermiogenesis in man. Somatic type histones are displaced by transition proteins which are replaced themselves by protamines, the major nuclear proteins present in late spermatids and sperm nuclei. Sense and antisense 35S-labelled riboprobes, coding respectively for human transition protein 1 (TP1) and protamine 1 (HP1), were synthesized with modified specific oligonucleotides and were used for light microscopy in situ hybridization. A double EM in situ hybridization was performed using a digoxigenin-labelled probe for TP1 and a biotin-labelled probe for HP1, and hybrids were revealed, respectively, with specific antibodies coupled to colloidal gold particles of different sizes (10 nm and 15 nm). For both types of transcripts, histological study revealed a specific distribution of the silver grains in the adluminal region of the seminiferous tubules where spermatids are localized. Quantitative ultrastructural analysis of the nuclear and cytoplasmic labelling densities for the mRNAs coding for TP1 and HP1 showed that the transcripts were found in both the nucleus and cytoplasm of round spermatids and persisted until the elongation phase. Transcripts accumulated in the spermatid cytoplasm without any particular cellular compartmentalization. At the end of the spermatid elongation phase, the disappearance of TP1 and HP1 transcripts may be related to the arrest of transcriptional activity, while the deposition of transition proteins and protamines occurs successively within spermatid nuclei.

Aged↗
PubMed1993

Transcriptional regulation in Drosophila during heat shock: a nuclear run-on analysis.

We used a nuclear run-on assay as a novel approach to study the changes in transcriptional activity that take place in Drosophila melanogaster during heat shock. In response to a rapid temperature upshift, total transcriptional activity in cultured KC161 cells decreased proportionally to the severity of the shock. After extended stress at 37 degrees C (15 min or more), transcription was severely reduced, and at 39 degrees C most transcription was instantaneously arrested. However, strikingly different responses were observed for individual genes. Transcription of histone H1 genes was severely inhibited even under mild heat shock conditions. Transcription of the actin 5C gene decreased progressively with increasing temperature, while transcription of the core histone genes or of the heat shock cognate genes was repressed only under severe heat shock conditions. Transcriptional activation of the D. melanogaster heat shock genes was also investigated. In unshocked cells, hsp84 was moderately transcribed, while transcriptional activity at the other protein-coding heat shock genes was undetectable (less than 0.2 polymerases per gene). Engaged but paused RNA polymerase molecules were found at the hsp70 and hsp26 genes, but not at the other heat shock genes. The rates of transcription increased with increasing temperature with a peak of expression at around 35 degrees C. At 37 degrees C, induction was less efficient, and no induction was achieved after a rapid shift to 39 degrees C. Increased transcription of the heat shock genes was observed within 1-2 min of heat shock, and maximal rates were reached within 2-5 min. Despite very similar profiles of response, different heat shock genes were transcribed at strikingly different rates, which varied over a 20-fold range. The noncoding heat shock locus 93D was transcribed at a very high rate under non-heat shock conditions, and showed a transcriptional response to elevated temperatures different from that of protein-coding heat shock genes. An estimation of the absolute rates of transcription at different temperatures was obtained.

Animals↗
PubMed1993

Presence of particular transcription regulatory elements in the 5'-intergenic region shared by the chicken H2A-III and H2B-V pair.

The two chicken histone gene families, H2A and H2B, contain nine and eight members, respectively, within two major histone gene clusters. Six genes each from families H2A and H2B have been found to be closely associated in inverted directions as H2A/H2B gene pairs. Two previously sequenced H2A members (H2A-I and H2A-II) encode the same amino acid (aa) sequence (class I), whereas seven sequenced H2B genes encode three different variants (classes I, II and III). In this study, we first sequenced H2A-III, a member of the H2A family, which is located in inverted orientation and 350 bp upstream from H2B-V, encoding the class-III H2B protein. The protein encoded by H2A-III differs from the class-I H2A protein in a single aa (Ala70-->Pro; class II). As a step toward elucidation of the transcriptional regulation of the H2A and H2B families, we fused this 5'-intergenic region to the cat gene in inverted orientations to generate two chimeric plasmids, pH2A-III-350 and pH2B-V-350. Transient CAT assays using these constructs indicated that the promoter of H2B-V is more active than that of H2A-III. CAT assays with 5'-deletion mutants of H2A-III and H2B-V showed that they each possess particular transcriptional motifs which are located relatively close to, or apart from, their own coding regions. These findings, together with those reported previously on the H2A-V/H2B-II pair, suggest distinct manners of transcription regulation of different members of the chicken histone gene families, H2A and H2B.

3T3 Cells↗
PubMed2004

A reciprocal translocation, induced by a canonical integration of a single T-DNA, interrupts the HMG-I/Y Arabidopsis thaliana gene.

Major chromosomal rearrangements occur during Arabidopsis thaliana T-DNA transformation. They generally result from interactions between multiple T-DNA copies during the integration process or from aborted integration events. We report here a reciprocal translocation associated with the integration of a single T-DNA which otherwise shows all the characteristic features of a canonical integration event. The exchanged fragments roughly correspond to half of the left arm of chromosome 1 and to two thirds of the right arm of chromosome 2. The chromosome 1 breakpoint maps close to position 23.6 cM and interrupts the coding sequence of the HMG-I/Y gene, which is present at a single copy in the Arabidopsis genome and encodes a non-histone chromosomal protein putatively involved in regulation of gene expression. The chromosome 2 breakpoint maps close to position 33.6 cM, and is located 419 bp upstream of a gene encoding a putative homeodomain transcription factor. Homozygotes for the translocation display a severe phenotype with major developmental abnormalities and total sterility, while heterozygotes are fertile, most of them showing a wild-type phenotype. Among the six possible unbalanced genotypic classes, four are entirely lethal while only a few individuals from the two others survive. Analysis of relations between phenotypes and genotypes strongly suggests that the major phenotypic alterations observed do not result from inactivation of the HMG-I/Y gene.

Arabidopsis↗
PubMed1983

Translational regulation of a specific gene during oogenesis and embryogenesis of Drosophila.

Polysomal and postpolysomal mRNAs were prepared from Drosophila egg chambers or embryos of different developmental stages. Cell-free translation of these mRNAs followed by two-dimensional gel electrophoresis of the products indicated the presence of a specific mRNA that appears to be translated (polysome-associated) during oogenesis. This mRNA, designated T1 mRNA, is selectively excluded from polysomes in 3-hr- and 5-hr-old embryos and is again translated in 18-hr-old embryos. A clone containing DNA complementary to T1 mRNA was selected from a library of recombinant DNA prepared from polyadenylylated ovary RNA. This clone was positively identified by hybrid-selected translation followed by two-dimensional gel electrophoresis and autoradiography. T1 mRNA is polyadenylylated and codes for a small, acidic protein. The cloned probe hybridizes to a unique site (2L-39CD) of the polytene chromosomes, very close to the histone genes. The results suggest that this mRNA is under specific translational regulation in contrast to a background of a large number of other abundant mRNAs that are translated at all developmental stages examined.

Journal Article↗