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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↗
PubMed2002

Evidence for repeat-induced gene silencing in cultured Mammalian cells: inactivation of tandem repeats of transfected genes.

Foreign DNA can be readily integrated into the genomes of mammalian embryonic cells by retroviral infection, DNA microinjection, and transfection protocols. However, the transgenic DNA is frequently not expressed or is expressed at levels far below expectation. In a number of organisms such as yeast, plants, Drosophila, and nematodes, silencing of transfected genes is triggered by the interaction between adjacent or dispersed copies of genes of identical sequence. We set out to determine whether a mechanism similar to repeat-induced gene silencing (RIGS) is responsible for the silencing of transgenes in murine embryonal carcinoma stem cells. We compared the expression of identical reporter gene constructs in cells carrying single or multiple copies and found that the level of expression per integrated copy was more than 10-fold higher in single-copy integrants. In cells carrying tandem copies of the transgene, many copies were methylated and clones frequently failed to express both copies of near-identical integrated alleles. Addition of extra copies of the reporter gene coding sequence reduced the level of expression from the same reporter driven by a eukaryotic promoter. We also found that inhibitors of histone deacetylase such as trichostatin A forestall the silencing of multicopy transgenes, suggesting that chromatin mediates the silencing of transfected genes. This evidence is consistent with the idea that RIGS does occur in mammalian embryonic stem cells although silencing of single-copy transgenes also occurs, suggesting that RIGS is only one of the mechanisms responsible for triggering transgene silencing.

Animals↗
PubMed1988

Two human genes isolated by a novel method encode DNA-binding proteins containing a common region of homology.

Two cDNAs encoding new DNA-binding proteins (Dbps) have been cloned using a human placenta lambda gt11 recombinant cDNA library and DNA fragments as probes. Hybrid proteins expressed by the lambda gt11 cDNA library were blotted onto nitrocellulose filters, and incubated with three different radio-labeled DNA probes containing the human epidermal growth factor (EGF) receptor enhancer or the human c-erbB-2 promoter. Two kinds of clones, named dbpA and dbpB, showed high affinities for the DNA probes. The comparison of the nucleotide and the deduced amino acid (aa) sequences between these two cDNAs indicated that 100 of 109 aa located in the central region of these two Dbps were identical. The dbpA and dbpB-coded proteins also had an affinity for other cDNA probes such as the human c-ski gene, but not for poly(dI-dC).poly(dI-dC), suggesting that the sequence(s) recognized by the dbpA and dbpB-coded proteins may occur frequently, or that these proteins bind to DNA non-specifically in a different manner from that of histones. A simple method, described in this paper, can be used to isolate cDNA clones encoding Dbps. Strategies used for the detection of sequence-specific and non-specific Dbps are discussed.

Amino Acid Sequence↗
PubMed2003

Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications.

Mitochondrial DNA (mtDNA) codes for 13 respiratory chain subunits and is more vulnerable to damage than nuclear DNA due, in part, to a lack of histone protection and a weak repair capacity. While mtDNA alterations have been observed in human cancer, their roles in oncogenesis and chemosensitivity remain unclear. We investigated the relationship between mtDNA mutations, reactive oxygen species (ROS) generation, and clinical outcomes in chronic lymphocytic leukemia (CLL) patients. An analysis of mtDNA from 20 CLL patients revealed that primary CLL cells from patients with prior chemotherapy had a significantly higher frequency of heteroplasmic mutations than did those from untreated patients. Overall, mtDNA mutations appeared to be associated with increased ROS generation. Patients refractory to conventional therapeutic agents tended to have higher mutation rates than patients who responded to treatment. Analysis of paired blood samples from the same patient led to the identification of a heteroplasmic mutation in the cytochrome c oxidase II gene several months after chemotherapy. The mutation was associated with increased ROS generation. Our results suggest for the first time that chemotherapy with DNA-damaging agents may cause mtDNA mutations in primary leukemia cells, which often exist in heteroplasmy, and are associated with increased ROS generation.

Adult↗
PubMed1996

Cloning and characterization of the major histone H2A genes completes the cloning and sequencing of known histone genes of Tetrahymena thermophila.

A truncated cDNA clone encoding Tetrahymena thermophila histone H2A2 was isolated using synthetic degenerate oligonucleotide probes derived from H2A protein sequences of Tetrahymena pyriformis. The cDNA clone was used as a homologous probe to isolate a truncated genomic clone encoding H2A1. The remaining regions of the genes for H2A1 (HTA1) and H2A2 (HTA2) were then isolated using inverse PCR on circularized genomic DNA fragments. These partial clones were assembled into intact HTA1 and HTA2 clones. Nucleotide sequences of the two genes were highly homologous within the coding region but not in the noncoding regions. Comparison of the deduced amino acid sequences with protein sequences of T. pyriformis H2As showed only two and three differences respectively, in a total of 137 amino acids for H2A1, and 132 amino acids for H2A2, indicating the two genes arose before the divergence of these two species. The HTA2 gene contains a TAA triplet within the coding region, encoding a glutamine residue. In contrast with the T. thermophila HHO and HTA3 genes, no introns were identified within the two genes. The 5'- and 3'-ends of the histone H2A mRNAs; were determined by RNase protection and by PCR mapping using RACE and RLM-RACE methods. Both genes encode polyadenylated mRNAs and are highly expressed in vegetatively growing cells but only weakly expressed in starved cultures. With the inclusion of these two genes, T. thermophila is the first organism whose entire complement of known core and linker histones, including replication-dependent and basal variants, has been cloned and sequenced.

Amino Acid Sequence↗
PubMed2019

Genome-wide analysis of polymerase III-transcribed Alu elements suggests cell-type-specific enhancer function.

Alu elements are one of the most successful families of transposons in the human genome. A portion of Alu elements is transcribed by RNA Pol III, whereas the remaining ones are part of Pol II transcripts. Because Alu elements are highly repetitive, it has been difficult to identify the Pol III-transcribed elements and quantify their expression levels. In this study, we generated high-resolution, long-genomic-span RAMPAGE data in 155 biosamples all with matching RNA-seq data and built an atlas of 17,249 Pol III-transcribed Alu elements. We further performed an integrative analysis on the ChIP-seq data of 10 histone marks and hundreds of transcription factors, whole-genome bisulfite sequencing data, ChIA-PET data, and functional data in several biosamples, and our results revealed that although the human-specific Alu elements are transcriptionally repressed, the older, expressed Alu elements may be exapted by the human host to function as cell-type-specific enhancers for their nearby protein-coding genes.

Alu Elements↗
PubMed1985

Localization of tyrosine kinase-coding region in v-abl oncogene by the expression of v-abl-encoded proteins in bacteria.

A series of plasmids containing different segments of the v-abl oncogene have been constructed to express different portions of the v-abl protein in bacteria. The tyrosine kinase activity of these proteins was determined by an in vitro assay employing histones or angiotensin II as substrates for the v-abl-encoded tyrosine kinase. These experiments show that the 5'-1.2 kilobases of v-abl is necessary and sufficient to produce an active tyrosine kinase which is functional as a monomeric soluble protein. The kinase-coding region corresponds to the minimal region of v-abl required for the transformation of fibroblasts. The kinase-coding region also coincides with the conserved protein sequences which are found in other tyrosine kinases. A compact domain of the v-abl protein including this kinase-coding region can accumulate to high levels in bacteria. The C-terminal region of the v-abl protein is not needed for the kinase activity and is rapidly degraded in bacteria.

Abelson murine leukemia virus↗
PubMed1990

The Tub alpha 3 gene from Zea mays: structure and expression in dividing plant tissues.

A gene (Tub alpha 3) coding for an alpha-Tub, expressed in dividing tissues, has been cloned from Zea mays. The deduced amino acid (aa) sequence, 450 aa long, is very similar to the other plant alpha-Tub (85-89% homology) so far reported, and in particular to the other two aa sequences (alpha 1-Tub and alpha 2-Tub) already published from the same species (93% homology). The genomic structure is also very similar, having three introns located at the same positions as in the Tub alpha 1 and Tub alpha 2 genes, one of them placed at the same position in the homologous genes from Arabidopsis thaliana. Nevertheless, the noncoding sequences are very different from the two other maize genomic sequences. In particular, no homology has been found either in the 5' upstream or in the 3'-untranslated sequences. Using specific 3' probes, it has been possible to detect the mRNA coded by this gene in many of the plant organs measured, but its highest abundance is observed in the organs rich in dividing cells, a pattern correlated with that of the histone H4-encoding gene. A cDNA clone has been identified in maize coleoptiles and sequenced, confirming the expression of the Tub alpha 3 in this organ. No preferential accumulation in any organ of the plant was found, in contrast with what was observed in the Tub alpha 1 and Tub alpha 2 genes already described. The Tub alpha gene family seems to consist in maize by at least two groups of homologous sequences, each one including a maximum of two or three coding units.

Amino Acid Sequence↗
PubMed1996

Differential effect of H1 variant overexpression on cell cycle progression and gene expression.

To identify functional differences among non-allelic variants of the mammalian H1 linker histones a system for the overexpression of individual H1 variants in vivo was developed. Mouse 3T3 cells were transformed with an expression vector containing the coding regions for the H1c or H10 variant under the control of an inducible promoter. Stable, single colony transformants, in which the normal stoichiometry of H1 variants was perturbed, displayed normal viability, unaltered morphology and no long-term growth arrest. However, upon release from synchronization at different points in the cell cycle transformants significantly overproducing H10 exhibited transient inhibition of both G1 and S phase progression. Overexpression of H1c to comparable levels had no effect on cell cycle progression. Analysis of transcript levels for several cell cycle-regulated and housekeeping genes indicated that overexpression of H10 resulted in significantly reduced expression of all genes tested. Surprisingly, overexpression of H1c to comparable levels resulted in either a negligible effect or, in some cases, a dramatic increase in transcript levels. These results support the suggestion that functional differences exist among H1 variants.

3T3 Cells↗
PubMed1987

Nucleoplasmin cDNA sequence reveals polyglutamic acid tracts and a cluster of sequences homologous to putative nuclear localization signals.

Nucleoplasmin is the most abundant protein in the Xenopus oocyte nucleus. It is involved in histone storage and chromatin assembly and it has been used extensively to study the transport of proteins into the cell nucleus. We have isolated lambda gt11 phage containing nucleoplasmin cDNA and have determined the sequence of the entire protein coding region of 200 amino acids for one of the two genes. The translation product of the sp6 transcript of this cDNA has the same electrophoretic mobility as nucleoplasmin and is able to form pentamers. The protein sequence shows remarkable clusters of charged residues including a long polyglutamic acid tract which presumably constitutes the histone binding site. The short C-terminal domain which specifies nuclear entry contains four regions which are homologous to putative nuclear localization signals including two regions of homology to the nuclear migration signal of SV40 large T antigen.

Amino Acid Sequence↗
PubMed1996

The chicken lysozyme gene 5' MAR and the Drosophila histone SAR are electroelutable from encapsulated and digested nuclei.

Cultured chicken cells were encapsulated in agarose microbeads, lysed in a near-physiological buffer and resulting encapsulated nuclei were digested with a restriction enzyme and electroeluted. After removal of approximately 97% of the chromatin, the nuclear lamina, residual nucleoli and an internal nuclear network remained. The majority of nascent RNA was also recovered in digested and electroeluted nuclei. Surprisingly, however, the chicken lysozyme gene 5' MAR was quantitatively electroeluted from digested nuclei of expressing and non-expressing cells, as well as the promoter region and the coding sequence. When encapsulated nuclei were digested partially, the proportion of elutable 5' MAR chromatin was comparable to that of elutable bulk chromatin. Furthermore, after digestion of encapsulated nuclei from Drosophila Kc cells, the histone SAR was electroeluted to the same extent as bulk chromatin. We conclude that the lysozyme gene 5' MAR and the histone SAR are not permanently attached to a nuclear matrix or scaffold.

Animals↗