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At least 793 records · Page 44Linked to original sources
PubMed2006

Expression of GATA-1 in a non-hematopoietic cell line induces beta-globin locus control region chromatin structure remodeling and an erythroid pattern of gene expression.

GATA-1 is a hematopoietic transcription factor expressed in erythroid, megakaryocytic, mast cell and eosinophil lineages. It is required for normal erythroid differentiation, the expression of erythroid-specific genes and for the establishment of an active chromatin structure throughout the beta-globin gene locus. GATA-1 is also necessary for the formation and function of the locus control region DNase I hypersensitive site (HS) core elements. To determine whether GATA-1 was sufficient to direct formation of the locus control region (LCR) and an erythroid pattern of gene expression, we expressed GATA-1 in the non-hematopoietic HeLa cell line that does not express other hematopoietic transcription factors but does express GATA-2, GATA-3, and GATA-6. We found that production of the GATA-1 protein resulted in the formation of LCR DNase I HSs 1-4 in their normal locations, and that histones became hyperacetylated within these regulatory elements. Transcription of several erythroid-specific genes was activated in HeLa cells expressing GATA-1, including those coding for alpha-globin, beta-globin, the erythropoietin receptor, the erythroid krüpple-like factor and p45 NF-E2. Despite increased expression of these genes at the mRNA level, their protein products were not detected. These results imply that GATA-1 is sufficient to direct chromatin structure reorganization within the beta-globin LCR and an erythroid pattern of gene expression in the absence of other hematopoietic transcription factors.

Acetylation↗
PubMed2005

Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes.

The treatment of cancer through the development of new therapies is one of the most important challenges of our time. The decoding of the human genome has yielded important insights into the molecular basis of physical disorders, and in most cases a connection between failures in specific genes and the resulting clinical symptoms can be made. The modulation of epigenetic mechanisms enables, by definition, the alteration of cellular phenotype without altering the genotype. The information content of a single gene can be crucial or harmful, but the prerequisite for a cellular effect is active gene transcription. To this end, epigenetic mechanisms play a very important role, and the transcription of a given gene is directly influenced by the modification pattern of the surrounding histone proteins as well as the methylation pattern of the DNA. These processes are effected by different enzymes which can be directly influenced through the development of specific modulators. Of course, all genetic information is written as a four-character code in DNA. However, epigenetics describes the art of reading between the lines.

Acetylation↗
PubMed1997

The gene for histone RNA hairpin binding protein is located on human chromosome 4 and encodes a novel type of RNA binding protein.

The hairpin structure at the 3' end of animal histone mRNAs controls histone RNA 3' processing, nucleocytoplasmic transport, translation and stability of histone mRNA. Functionally overlapping, if not identical, proteins binding to the histone RNA hairpin have been identified in nuclear and polysomal extracts. Our own results indicated that these hairpin binding proteins (HBPs) bind their target RNA as monomers and that the resulting ribonucleoprotein complexes are extremely stable. These features prompted us to select for HBP-encoding human cDNAs by RNA-mediated three-hybrid selection in Saccharomyces cerevesiae. Whole cell extract from one selected clone contained a Gal4 fusion protein that interacted with histone hairpin RNA in a sequence- and structure-specific manner similar to a fraction enriched for bovine HBP, indicating that the cDNA encoded HBP. DNA sequence analysis revealed that the coding sequence did not contain any known RNA binding motifs. The HBP gene is composed of eight exons covering 19.5 kb on the short arm of chromosome 4. Translation of the HBP open reading frame in vitro produced a 43 kDa protein with RNA binding specificity identical to murine or bovine HBP. In addition, recombinant HBP expressed in S. cerevisiae was functional in histone pre-mRNA processing, confirming that we have indeed identified the human HBP gene.

Amino Acid Sequence↗
PubMed1985

Organization, primary structure, and evolution of histone H2A and H2B genes of the fission yeast Schizosaccharomyces pombe.

The histone H2A and H2B genes of the fission yeast Schizosaccharomyces pombe were cloned and sequenced. Southern blot and sequence analyses showed that, unlike other eucaryotes, Saccharomyces cerevisiae included, S. pombe has unequal numbers of these genes, containing two histone H2A genes (H2A-alpha and -beta) and only one H2B gene (H2B-alpha) per haploid genome. H2A- and H2B-alpha are adjacent to each other and are divergently transcribed. H2A-beta has no other histone gene in close proximity. Preceding both H2A-alpha and -beta is a highly conserved 19-base-pair sequence (5'-CATCAC/AAACCCTAACCCTG-3'). The H2A DNA sequences encode two histone H2A subtypes differing in amino acid sequence (three residues) and size (H2A-alpha, 131 residues; H2A-beta, 130 residues). H2B-alpha codes for a 125-amino-acid protein. Sequence evolution is extensive between S. pombe and S. cerevisiae and displays unique patterns of divergence. Certain N-terminal sequences normally divergent between eucaryotes are conserved between the two yeasts. In contrast, the normally conserved hydrophobic core of H2A is as divergent between the yeasts as between S. pombe and calf.

Amino Acid Sequence↗
PubMed1989

Expression of a mouse replacement histone H3.3 gene with a highly conserved 3' noncoding region during SV40- and polyoma-induced Go to S-phase transition.

We have isolated and sequenced a mouse replacement variant histone H3.3 cDNA. It corresponds to the most abundant mRNA expressed from a unique gene by the use of one out of three polyadenylation sites. The 3' non coding region of H3.3 is very long (approximately 1100 nt) and highly conserved throughout evolution since it is about 95% homologous to the 3' non coding region of the chicken H3.3B gene. We studied the expression of the H3.3 gene during SV40- and polyoma-induced mitotic host reaction in confluent, Go-arrested primary mouse kidney cell cultures. H3.3 replacement variant mRNA steady state levels increased during the Go to S-phase transition, apparently as the result of two mechanisms: one related to cell growth, whereas the other was linked to cellular DNA synthesis. The latter mechanism was however far less pronounced than with replication histone variant mRNAs. The biological implications of these results are discussed.

Amino Acid Sequence↗
PubMed2005

Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line.

The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells.

Acetylation↗
PubMed2003

Scaffold attachment factor A (SAF-A) is concentrated in inactive X chromosome territories through its RGG domain.

Female mammalian cells inactivate transcription from one of their X chromosomes to equalize gene expression of X-linked genes between males and females. Inactivation is a multistep process that involves a large non-coding RNA termed XIST, a variety of epigenetic modifications of chromatin, and alterations in protein composition such as enrichment of the histone variant macroH2A. We show here that inactive X chromosomes are also enriched in a well-characterized protein component of the nuclear scaffold, SAF-A. This protein has been implicated in chromatin organization, owing to its high specificity for scaffold-associated region (SAR)-DNA, in transcriptional regulation, e.g. of hormone-regulated genes, owing to its functional interaction with steroid receptors, and in RNA processing, owing to its interaction with RNA and heterogeneous nuclear ribonucleoprotein (hnRNP) particles. After near complete removal of DNA and associated chromatin proteins such as macroH2A, SAF-A remains with the "nuclear matrix", still highlighting the former position of inactive X chromosomes. Interestingly, the enrichment of SAF-A in the inactive X chromosome depends on the RNA binding domain of the protein, the RGG box, raising the possibility that interaction of SAF-A with XIST RNA may contribute to the silencing of X-linked genes by local changes in nuclear architecture.

Cells, Cultured↗
PubMed1993

Construction of nucleosome cores from defined sequence DNA of viral origin.

The de novo construction of defined nucleosomes from two DNA fragments of simian virus SV40 is described. One fragment spans the region containing the origin of replication of the virus from base -16 to base 161, a region which is nucleosome-free during virus replication. The other fragment, of 142 bp (1352 to 1493), is within the region coding for viral proteins VP2 and VP3, and serves for comparison. Both fragments form nucleosomes with similar efficiency when combined with histone cores as well as when exchanged with existing core particles. The DNase I digestion pattern and exonuclease III analysis both indicate that true nucleosome cores are formed, and that a prolonged tail is not protruding from the constructs. The efficient formation of a nucleosome core particle from the origin region of DNA implies that the absence of nucleosomes from this region during viral infection is not prescribed by the specific base sequence of origin DNA, and is therefore likely to be determined by non-histone nuclear factors associated with the SV40 replication process.

Base Sequence↗
PubMed1991

Nucleotide sequences of two members of the chicken H4 histone-encoding gene family.

The nucleotide sequences of two genes (H4-III and H4-IV) from the chicken H4 histone-encoding gene family have been determined. The four H4 genes, including the previously sequenced H4-I and H4-II genes, encode the same amino acid sequence and possess several copies of the possible Sp1-binding sequences on the coding and noncoding strands within the 5'-flanking regions.

Amino Acid Sequence↗
PubMed1989

Characterization of poly(ADP-ribosyl)ated domains of rat pachytene chromatin.

Poly(ADP-ribosyl)ation of nuclear proteins was several-fold higher in the pachytene spermatocytes than in the premeiotic germ cells of the rat. Among the histones of the pachytene nucleus, histone subtypes H2A, H1 and H3 were poly(ADP-ribosyl)ated. Based on the immunoaffinity fractionation procedure of Malik, Miwa, Sugimara & Smulson [(1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2554-2558] we have fractionated DNAase-II-solubilized chromatin into poly(ADP-ribosyl)ated chromatin (PAC) and non-poly(ADP-ribosyl)ated chromatin (non-PAC) domains on an anti-[poly(ADP-ribose)] IgG affinity matrix. Approx. 2.5% of the pachytene chromatin represented the PAC domains. A significant amount of [alpha-32P]dATP-labelled pachytene chromatin (labelled in vitro) was bound to the affinity matrix. The DNA of pachytene PAC domains had internal strand breaks, significant length of gaps and ligatable ends, namely 5'-phosphoryl and 3'-hydroxyl termini. On the other hand, the PAC domains from 18 h regenerating liver had very few gaps, if any. The presence of gaps in the pachytene PAC DNA was also evident from thermal denaturation studies. Although many of the polypeptides were common to the PAC domains of both pachytene and regenerating liver, the DNA sequences associated with these domains were quite different. A 20 kDa protein and the testis-specific histone H1t were selectively enriched in the pachytene PAC domains. The pachytene PAC domains also contained approx. 10% of the messenger coding sequences present in the DNAase-II-solubilized chromatin. The pachytene PAC domains, therefore, may represent highly enriched DNA-repair domains of the pachytene nucleus.

Animals↗
PubMed1990

A genomic clone encoding a novel proliferation-dependent histone H2A.1 mRNA enriched in the poly(A)+ fraction.

Replication-dependent histone mRNAs are prime examples of nonpolyadenylated mRNAs. We isolated and characterized cDNAs and a genomic clone for a replication-dependent histone H2A.1 mRNA which segregated into the poly(A)+ fraction during mRNA isolation through an oligo(dT)-cellulose column. However, the results of sequencing of the genomic clone suggested that the mRNA did not contain a poly(A) tail. Instead, the genomic sequence revealed a nonterminal oligo(A) tract directly upstream from the typical 3'-terminal hairpin loop of replication-dependent histone mRNAs. The nonterminal oligo(A) tract consisted of 14 adenylate residues interrupted by one guanylate residue (A4GA10). We concluded that this short oligo(A) stretch mediated binding of the mRNA to oligo(dT) even after stringent washes with 0.1 M NaCl, indicating that rather short oligo(A) sequences can ensure binding to oligo(dT)-cellulose. The cDNA and genomic clones contained an AAATAAG sequence at the end of the coding region. It has been suggested that this sequence contains a polyadenylation signal in some yeast and mouse transcripts, but it does not function as a polyadenylation signal in the histone transcript described in this paper.

Amino Acid Sequence↗
PubMed2003

Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity.

Set1, the yeast histone H3-lysine 4 (H3-K4) methylase, is recruited by the Pol II elongation machinery to a highly localized domain at the 5' portion of active mRNA coding regions. Set1 association depends upon the TFIIH-associated kinase that phosphorylates the Pol II C-terminal domain (CTD) and mediates the transition between initiation and elongation, and Set1 interacts with the form of Pol II whose CTD is phosphorylated at serine 5 but not serine 2. The Rtf1 and Paf1 components of the Pol II-associated Paf1 complex are also important for Set1 recruitment. Although the level of dimethylated H3-K4 is fairly uniform throughout the genome, the pattern of trimethylated H3-K4 strongly correlates with Set1 occupancy. Hypermethylated H3-K4 within the mRNA coding region persists for considerable time after transcriptional inactivation and Set1 dissociation from the chromatin, indicating that H3-K4 hypermethylation provides a molecular memory of recent transcriptional activity.

Blotting, Western↗
PubMed1990

Crystallization of the globular domain of histone H5.

The globular domain of histone H1/H5 binds to the nucleosome and is crucial for the formation of chromatin higher order structure. We have expressed in Escherichia coli a gene that codes for the globular domain of H5. The protein produced in E. coli is functional in nucleosome binding assays. We have obtained crystals of the protein that diffract to beyond 2.5 A (1 A = 0.1 nm) resolution. The crystals are orthorhombic with unit cell dimensions of a = 80.1 A, b = 67.5 A and c = 38.0 A.

Crystallization↗
PubMed1976

The relative positions of sea urchin histone genes on the chimeric plasmids pSp2 and pSp17 as studied by electronmicroscopy.

The relative positions of the sea urchin histone genes and the spacer regions on the chimeric plasmids pS p2 and pSp17 have been mapped by hybridizing total histonemessenger RNA to single strands of the plasmid DNAs. The lengths and spacing between the several RNA:DNA duplex regions on the single strands of DNA were measured by the gene 32-ethidium bromide electron microscope mapping method. We find that the genes are interdigitated with spacer sequences of different lengths; that there are three coding sequences on pSp2, all on the same strand, with the relative order H1, H4, and B4; and that there are two coding sequences on pSp17, both on the same strand, corresponding to the messages denoted B1 and B2-B3, where B4, B1, and B2-3 are electrophoretically resolved components of histone mRNA, all of size intermediate between the larger H1 and the smaller H4 message.

Chimera↗
PubMed2000

Chromodomains are protein-RNA interaction modules.

In Drosophila, compensation for the reduced dosage of genes located on the single male X chromosome involves doubling their expression in relation to their counterparts on female X chromosomes. Dosage compensation is an epigenetic process involving the specific acetylation of histone H4 at lysine 16 by the histone acetyltransferase MOF. Although MOF is expressed in both sexes, it only associates with the X chromosome in males. Its absence causes male-specific lethality. MOF is part of a chromosome-associated complex comprising male-specific lethal (MSL) proteins and at least one non-coding roX RNA. How MOF is integrated into the dosage compensation complex is unknown. Here we show that association of MOF with the male X chromosome depends on its interaction with RNA. MOF specifically binds through its chromodomain to roX2 RNA in vivo. In vitro analyses of the MOF and MSL-3 chromodomains indicate that these chromodomains may function as RNA interaction modules. Their interaction with non-coding RNA may target regulators to specific chromosomal sites.

Acetyltransferases↗
PubMed1991

Isolation and characterization of a cDNA from a human histone H2B gene which is reciprocally expressed in relation to replication-dependent H2B histone genes during HL60 cell differentiation.

A variant human histone H2B cDNA (HHC289) has been cloned and characterized and shown to have a complex pattern of regulation with respect to the HeLa S3 cell cycle and HL60 cell differentiation. The H2B protein coding region of HHC289 is flanked at the 3' end by a 1798-nt nontranslated trailer that contains a region of hyphenated dyad symmetry and a poly(A) addition sequence, followed by a poly(A) tail. Nuclear run-on transcription analysis revealed a 2-fold increase in transcription of the HHC289 gene during S phase, in comparison to replication-dependent human histone genes which exhibit a 2-3-fold increase in transcription during S phase. Northern blot analysis indicated that the levels of the 2300-nt HHC289 mRNA species did not vary significantly during the HeLa S3 cell cycle, in comparison to replication-dependent H2B mRNAs which are elevated 15-fold during S phase. Northern blot analysis also revealed a reciprocal relationship during the onset of HL60 differentiation between the expression of the HHC289 H2B gene and the replication-dependent H2B genes. The levels of the 2300-nt HHC289 H2B species increased approximately 10-fold during HL60 cell differentiation whereas the levels of cell cycle dependent H2B mRNAs decreased to less than 1% of those in proliferating cells. These results suggest that complex transcriptional and posttranscriptional regulatory mechanisms control cellular levels of mRNAs from various human H2B histone genes during progression through the cell cycle and at the onset of differentiation.

Amino Acid Sequence↗
PubMed1983

A proposed model of cancer as the inappropriate expression of non-body introns.

An a posteriori proposal is made that cancer represents an alien non-body phenotype erupting from "silent" gene groups within actively coding regions of a normal cell's genome. Relevant empirical data is garnered from the literature and twelve premises are derived from the data. On the basis of these premises it is hypothesized that the malignant neoplastic phenotype results from interference with non-histone chromosomal proteins causing retention and expression in a body cell of non-body introns. These are asserted to be the same introns which, as exons in a trophoblast cell, direct the normal development of the fetal placenta. Development of a malignant tumor is presented as a pathological recapitulation of the development of a normal placenta. Unrestrained tumor growth is attributed to the inability of endogenous body chalones to suppress the non-body gene groups coding for neoplastic mitosis, while invasion and metastasis result from failure of the non-body genes which code for implantation and mitosis to switch off at the proper time. The hypothesis asserts that all carcinogenic agents alter phosphorylation of non-histone chromosomal proteins, that cancer and normal trophoblast cells are genetically programmed to travel through the body's vascular system to effect immunosuppression in lymphoid tissues, that malignant neoplastic tissue will regress when exposed to trophoblast-based chalones, and that mammals immunized against trophoblast-based antigen will be resistant to the development of malignant tumors.

Animals↗
PubMed1987

Molecular cloning of cDNA coding for rat proliferating cell nuclear antigen (PCNA)/cyclin.

The 'proliferating cell nuclear antigen' (PCNA), also known as cyclin, appears at the G1/S boundary in the cell cycle. Because of its possible relationship with cell proliferation, PCNA/cyclin has been receiving attention. PCNA/cyclin is a non-histone acidic nuclear protein with an apparent mol. wt of 33000-36000. The amino acid composition and the sequence of the first 25 amino acids of rabbit PCNA/cyclin are known. Using an oligonucleotide probe corresponding to the sequence of the first five amino acids, a cDNA clone for PCNA/cyclin was isolated from rat thymocyte cDNA library. The cDNA (1195 bases) contains an open reading frame of 813 nucleotides coding for 261 amino acids. The 3'-non-coding region is 312 nucleotides long and contains three putative polyadenylation signals. The mol. wt of rat PCNA/cyclin was calculated to be 28 748. The deduced amino acid sequence and composition of rat PCNA/cyclin are in excellent agreement with the published data. Using the cDNA probe, two species of mRNA (1.1 and 0.98 kb) were detected in rat thymocyte RNA. Southern blot analysis of total human genomic DNA suggests that there is a single gene coding for PCNA/cyclin. The deduced amino acid sequence of rat PCNA/cyclin has a similarity with that of herpes simplex virus type-1 DNA binding protein.

Amino Acid Sequence↗