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PubMed1993

The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression.

We have immunolabeled human and mouse metaphase chromosomes with antibodies specific for the acetylated isoforms of histone H4. All chromosomes were labeled in regions corresponding to conventional R bands (regions enriched in coding DNA), except for a single chromosome in female cells, which was largely unlabeled and which we have identified as the inactive X (Xi). Three sharply defined immunofluorescent bands, enhanced by butyrate pretreatment, were observed in homologous positions on the human and mouse Xi, showing limited, regional persistence of H4 acetylation. Two of these bands are in cytogenetic regions known to contain genes expressed on Xi. We propose that H4 hyperacetylation defines regions of the genome containing potentially transcriptionally active chromatin, while virtual absence of H4 acetylation defines both constitutive and facultative heterochromatin.

Acetylation↗
PubMed2002

Effects of histone acetylation and DNA methylation on p21( WAF1) regulation.

Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.

Acetylation↗
PubMed1987

Molecular cloning of a pea H1 histone cDNA.

A pea (Pisum sativum, var. Little Marvel) H1 histone cDNA has been isolated from a lambda gt11 expression vector library. This cDNA has been sequenced and shown to represent the entire protein-coding region of the mRNA. The deduced protein sequence is 265 amino acids long (28018 Da) and contains 70 lysines and 3 arginines. The structure of the encoded protein is comparable to animal lysine-rich histones. The central region, which has an amino acid composition similar to that found in the globular domains of animal lysine-rich histones, is flanked by an amino-terminal region rich in lysine, glutamic acid and proline and by a carboxyl-terminal region rich in lysine, alanine, valine and proline. Despite the structural similarities, the protein has little sequence homology with animal lysine-rich histones. This H1 protein is unusual because 12 of the first 40 amino acids are glutamic acid.

Amino Acid Sequence↗
PubMed1994

The H1A histone variant is an in vivo repressor of oocyte-type 5S gene transcription in Xenopus laevis embryos.

Previous in vitro transcription studies have pointed to the importance of histone H1 for repression of oocyte-type 5S genes of Xenopus laevis. It has been previously reported that in development up to the early gastrula stage, Xenopus embryos contain a large pool of the maternal histone H1 variant H1M but are virtually devoid of histone H1A, H1B, and H1C proteins. At the early gastrula stage, there is an increase in H1A protein synthesis and H1A becomes the predominant H1 histone variant. Concomitant with the significant appearance of H1A protein in chromatin, oocyte 5S transcription is repressed. Here it is shown that there appears to be a direct link between H1A accumulation and inhibition of oocyte-type 5S RNA synthesis. Inhibition of H1A synthesis by a ribozyme targeted to H1A mRNA leads to the continued expression of oocyte 5S genes. H1A is proposed to inhibit major oocyte 5S gene transcription by sealing the nucleosome that is positioned over the major oocyte 5S coding sequences and by driving major oocyte 5S gene chromatin into a higher-order structure in which histone H1A molecules interact cooperatively.

Animals↗
PubMed2006

H4 acetylation does not replace H3 acetylation in chromatin remodelling and transcription activation of Adr1-dependent genes.

Histone acetylation regulates gene expression. Whether this is caused by a general increase in nucleosome fluidity due to charge neutralization or by a more specific code is still matter of debate. By using a set of glucose-repressed Adr1-dependent genes of Saccharomyces cerevisiae, whose transcription was previously shown to require both Gcn5 and Esa1, we asked how changes of histone acetylation patterns at the promoter nucleosomes regulate chromatin remodelling and activation. When the signal of glucose reduction reaches the cells, H4 acetylation is kept constant while an increase of H3 acetylation occurs, in an Adr1- and Gcn5-dependent manner. In cells lacking Gcn5 activity, the H3 acetylation increase does not occur and an unexpected increase of histone H4 acetylation is observed. Nevertheless, chromatin remodelling and transcription activation are impaired, suggesting that acetylation of H3 and H4 histones plays different roles.

Acetylation↗
PubMed1979

Characterization of a histone-like protein extracted from yeast mitochondria.

Analysis of proteins isolated by affinity chromatography on DNA-cellulose from highly purified yeast mitochondria shows that these organelles do not contain histones but have in abundance a DNA-binding protein of 20,000 daltons. The purification yield of this protein, called HM, indicates that mitochondria have at least an equal mass of HM relative to DNA. The amino acid composition and its electrophoretic characterization reveal that HM, rich in lysine, is slightly basic and heat stable. HM appears to be coded by the yeast nucleus, as shown by its presence in several "petite" mutants. We have shown that HM, like histones or histone-like proteins, is able to introduce superhelical turns into circular relaxed DNA in the presence of a nicking-closing activity.

Amino Acids↗
PubMed1980

Late modifications of simian virus 40 chromatin during the lytic cycle occur in an immature form of virion.

Two main modifications of the simian virus 40 chromatin were found to occur during the lytic cycle. One was the progressive increase in the acetylation level in the four non-H1 histones as the 75S deoxynucleoprotein complexes (minichromosomes) became assembled into heavier structures. The other was the final elimination from viral chromatin of histone H1. An important stage in the course of these changes was represented by an intracellular simian virus 40 particle, in which the virus-coded proteins were already assembled, but properties distinct from those of mature virions were still present. This particle resembled the mature virions in morphology, sedimentation rate, and buoyant density. It was distinguished by the instability, the presence of histone H1, the uptake of radioactive acetate, and the lower infectivity. Its significance appears to be that of an immature virion on the basis of these characters and of the consistent kinetic behavior during the lytic cycle.

Acetylation↗
PubMed2005

Histone modifications: from genome-wide maps to functional insights.

A large number of histone modifications has been implicated in the regulation of gene expression. Together, these modifications have the potential to form a complex combinatorial regulatory code. Genome-wide mapping approaches provide new opportunities to decipher this code, but they may suffer from systematic biases. Integration of datasets and improved technologies will provide the way forward.

Acetylation↗
PubMed1997

Characterization of the H1.5 gene completes the set of human H1 subtype genes.

The H1 histone family in mammals contains at least seven subtypes. In the past we have isolated six of the seven genes encoding these isoforms. To complete the set of the human H1 histone genes, we have designed two PCR primers deduced from a partially published sequence of the remaining histone H1 gene [Carozzi et al. (1984) Science 224, 1115-1118] and from a consensus sequence which we have derived from the conserved region of human histone H1 genes. Using these primers we have amplified a 417-bp DNA fragment from total human DNA. This fragment was used for screening a human phage genomic library. Two overlapping clones were isolated. The region contains a set of 5 genes representing each of the five histone classes. In continuation of our numbering of human H1 genes, we have named this H1 gene H1.5. This gene encodes a protein almost identical to the previously published protein sequence designated H1a [Ohe et al. (1986) J. Biochem. 100, 359-368]; since the changes are in a region of some uncertainty of the peptide sequencing, we conclude that the newly isolated gene codes for the H1a protein. The structures of the flanking regions of the genes except the H2B gene are typical for histone genes. They include: (1) a CCAAT element in the promotor region, (2) a TATA box and (3) a palindromic termination element. The H2B sequence shows no typical regulatory elements and no complete ORF, therefore we consider it as a pseudogene. The expression of the H1.5 gene was examined in several cell lines.

Amino Acid Sequence↗
PubMed2000

Transcription through nucleosomes.

Transcriptionally active genes in eukaryotes still retain most of the Chromatin packaging that is characteristic of eukaryotic DNA. Nucleosomes and even some higher order structure are present, although the histones may be chemically modified, for example by acetylation or phosphorylation, as part of the activation process. The presence of nucleosomes on the coding region of active genes raises the question: How does an RNA polymerase transcribe such a template? We have attempted to answer this question with relatively simple model systems involving a template carrying a single positioned nucleosome. We have shown that when a phage polymerase, SP6, transcribes such a template, the histone octamer of the nucleosome is not released into solution. Instead it is retained on the same DNA molecule, but displaced from its original binding site. Further studies have allowed us to propose a detailed model, which appears to hold not only for SP6 but also for transcription by the much larger RNA polymerase III from yeast. Our most recent results, obtained by electron cryomicroscopy, confirm and refine this model.

DNA↗
PubMed1990

Characterization of the promoter region of Tetrahymena genes.

The regions between adjacent histone H3 and H4 genes, as well as portions of the genes, from 22 species of Tetrahymena have been amplified using the polymerase chain reaction and sequenced. Both histone genes are transcribed divergently with initiation occurring within the intergenic region, thus 2 sets of 22 homologous Tetrahymena promoters can be compared. A sequence comparison of these regions reveals a single putative promoter element, with a consensus sequence TATCCAATTCARA, present in front of each gene. This sequence contains a 'CCAAT' box, which also occurs at 8 locations preceding other ciliate genes. No other putative promoter sequences are found in front of these sets of histone genes. Sequences searched for include 'TATA' boxes, 'GC' boxes and other sequences suggested as putative promoter elements for ciliate genes. The coding strand immediately preceding ciliate genes is very high in A content and the consensus sequence at the site of protein synthesis is AAAATGG.

Animals↗
PubMed1990

Potential genetic functions of tandem repeated DNA sequence blocks in the human genome are based on a highly conserved "chromatin folding code".

This review is based on a thorough description of the structure and sequence organization of tandemly organized repetitive DNA sequence families in the human genome; it is aimed at revealing the locus-specific sequence organization of tandemly repetitive sequence structures as a highly conserved DNA sequence code. These repetitive so-called "super-structures" or "higher-order" structures are able to attract specific nuclear proteins. I shall define this code therefore as a "chromatin folding code". Since locus-specific superstructures of tandemly repetitive sequence units are present not only in the chromosome centromere or telomere region but also on the arms of the chromosomes, I assume that their chromatin folding code may contribute to, or even organize, the folding pathway of the chromatin chain in the nucleus. The "chromatin folding code" is based on its specific "chromatin code", which describes the sequence dependence of the helical pathway of the DNA primary sequence (i.e., secondary structure) entrapping the histone octamers in preferential positions. There is no periodicity in the distribution of the nucleosomes along the DNA chain. The folding pathway of the nucleosomal chromatin chain is however still flexible and determined by e.g., the length of the DNA chain between the nucleosomes. The fixation and stabilization of the chromatin chain in the space of the nucleus (i.e., its "functional state") may be mediated by additionally unique DNA protein interactions that are dictated by the "chromatin folding code". The unique DNA-protein interactions around the centromeres of human chromosomes are revealed for example by their "C-banding". I wish to stress that it is not my aim to relate each block of repetitive DNA sequences to a specific "chromatin folding code", but I shall demonstrate that there is an inherent potential for tandem repeated sequence units to develop a locus-specific repetitive higher order structure; this potential may create a specific chromatin folding code whenever a selection force exists at the position of this repetitive DNA structure in the genome.

Chromatin↗
PubMed1988

The matrix attachment regions of the chicken lysozyme gene co-map with the boundaries of the chromatin domain.

The matrix attachment regions of the chicken lysozyme domain were studied in an in vitro DNA binding assay by incubating oviduct nuclear matrices with labeled restriction fragments. A strong attachment region was localized between 11.1 and 8.85 kb upstream of the transcription start site and a weaker one between 1.3 and 5.0 kb downstream of the poly(A)+ addition site. Both attachment regions co-map with the previously established boundaries of the chromatin domain. The upstream matrix attachment region is distinguishable from known enhancers and is composed of multiple binding sites. We find specific but weaker binding of the same restriction fragments to matrix preparations from transcriptionally inactive chicken erythrocytes indicating a cell-type and transcription-independent conservation of the sites for specific binding of matrix attachment sequences. We also demonstrate that the matrix attachment regions are located at the base of a chromosomal loop in histone-extracted nuclei. Thus, the lysozyme domain represents a topologically-sequestered functional unit containing the coding region and all known lysozyme-specific, cis-acting regulatory elements.

Animals↗
PubMed1998

Thermoregulation of Escherichia coli pap transcription: H-NS is a temperature-dependent DNA methylation blocking factor.

The expression of Pap pili that facilitate the attachment of Escherichia coli to uroepithelial cells is shut off outside the host at temperatures below 26 degrees C. Ribonuclease protection analysis showed that this thermoregulatory response was rapid as evidenced by the absence of papBA transcripts, coding for Pap pilin, after only one generation of growth at 23 degrees C. The histone-like nucleoid structuring protein H-NS and DNA sequences within papB were required for thermoregulation, but the PapB and PapI regulatory proteins were not. In vivo analysis of pap DNA methylation patterns indicated that H-NS or a factor regulated by H-NS bound within the pap regulatory region at 23 degrees C but not at 37 degrees C, as evidenced by H-NS-dependent inhibition of methylation of the pap GATC sites designated GATC-I and GATC-II. These GATC sites lie upstream of the papBAp promoter and have been shown previously to play a role in controlling Pap pili expression by regulating the binding of Lrp, a global regulator that is essential for activating papBAp transcription. Competitive electrophoretic mobility shift analysis showed that H-NS bound specifically to a pap DNA fragment containing the GATC-I and GATC-II sites. Moreover, H-NS blocked methylation of these pap GATC sites in vitro: H-NS blocked pap GATC methylation at 1.4 microM but was unable to do so at higher concentrations at which non-specific binding occurred. Thus, non-specific binding of H-NS to pap DNA was not sufficient to inhibit methylation of the pap GATC sites. These results suggest that the ability of H-NS to act as a methylation blocking factor is dependent upon the formation of a specific complex of H-NS with pap regulatory DNA. We hypothesize that a function of H-NS such as oligomerization was altered at 23 degrees C, which enabled H-NS to repress pap gene expression through the formation of a specific nucleoprotein complex.

Artificial Gene Fusion↗
PubMed1999

The HMG-I(Y) A.T-hook peptide motif confers DNA-binding specificity to a structured chimeric protein.

Chromosomal translocations involving genes coding for members of the HMG-I(Y) family of "high mobility group" non-histone chromatin proteins (HMG-I, HMG-Y, and HMG-IC) have been observed in numerous types of human tumors. Many of these gene rearrangements result in the creation of chimeric proteins in which the DNA-binding domains of the HMG-I(Y) proteins, the so-called A.T-hook motifs, have been fused to heterologous peptide sequences. Although little is known about either the structure or biophysical properties of these naturally occurring fusion proteins, the suggestion has been made that such chimeras have probably assumed an altered in vivo DNA-binding specificity due to the presence of the A.T-hook motifs. To investigate this possibility, we performed in vitro "domain-swap" experiments using a model protein fusion system in which a single A. T-hook peptide was exchanged for a corresponding length peptide in the well characterized "B-box" DNA-binding domain of the HMG-1 non-histone chromatin protein. Here we report that chimeric A. T-hook/B-box hybrids exhibit in vitro DNA-binding characteristics resembling those of wild type HMG-I(Y) protein, rather than the HMG-1 protein. These results strongly suggest that the chimeric fusion proteins produced in human tumors as a result of HMG-I(Y) gene chromosomal translocations also retain A.T-hook-imparted DNA-binding properties in vivo.

Amino Acid Sequence↗
PubMed2005

Transcriptional regulation of neuronal genes and its effect on neural functions: gene expression in response to static magnetism in cultured rat hippocampal neurons.

We have previously shown a marked but transient increase in DNA binding of the nuclear transcription factor activator protein-1 after brief exposure to static magnetic fields in cultured rat hippocampal neurons, suggesting that exposure to static magnetism would lead to long-term consolidation as well as amplification of different functional alterations through modulation of de novo protein synthesis at the level of gene transcription in the hippocampus. Hippocampal neurons were cultured under sustained exposure to static magnetic fields at 100 mT, followed by extraction of total RNA for differential display (DD) analysis using random primers. The first and the second DD polymerase chain reaction similarly showed the downregulation of particular genes in response to sustained magnetism. Nucleotide sequence analysis followed by BLASTN homology searching revealed high homology of these 2 DD-PCR products to the 3' non-coding regions of the mouse basic helix-loop-helix transcription factor ALF1 and that of histone H3.3A, respectively. On Northern blot analysis using the 2 cloned differentially expressed fragments labeled with [alpha-(32)P]dCTP by the random primer method, a marked decrease was seen in expression of mRNA for ALF1 and histone H3.3A in hippocampal neurons cultured under sustained exposure to static magnetic fields at 100 mT. It thus appears that static magnetism may modulate cellular integrity and functionality through expression of a variety of responsive genes required for gene transcription and translation, proliferation, differentiation, maturation, survival, and so on in cultured rat hippocampal neurons.

Animals↗