[Expression and selection of messenger RNA].
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Animals↗
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The rate of change of DNA in evolution.
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Amino Acid Sequence↗
[Metaplasia as a problem of somatic cell genetics].
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Adaptation, Biological↗
Two independently inherited electrophoretic variants of the lysine-rich histones of maize (Zea mays).
We report here the first instance of inherited intraspecific histone variation in plants. Maize lysine-rich histone I is composed of four subfractions that are electrophoretically distinct in long polyacrylamide gels. Initial segregation studies indicate that at least one subfraction shows mobility differences inherited as if controlled by a single Mendelian locus. The locus is not on the short arms of chromosomes 2 or 4. The third subfraction also shows variants. Indirect evidence indicates that the genes controlling the variants of this subfraction segregate independently of those of the first. We suggest the symbols alh-A188 and alh-W23 to designate two of the alleles we have discovered of the first subfraction (a) of the lysine-rich histones and clh-A188 and clh-W23 the alleles of the third subfraction (c) of the lysine-rich histones. Other strains of maize show other differences in their histone I fractions, suggesting that there is inbredline-specific polymorphism with respect to histone I variants. The meiotic chromosome mutants, elongate and sticky, do not appear to condition maize histone alterations that can be detected electrophoretically.
Alleles↗
[Prediction in histones of the DNA-recognizing protein superstructure alpha helix-turn-alpha helix].
The localization of DNA-recognizing supersecondary structure alpha-helix--turn--alpha-helix in 85 amino acid sequences of histones is predicted. According to the prediction method based on the necessary requirements of amino acid coding this structure may be localized in the following segments of amino acid sequences of calf thymus histones: H1--90--112, H2A--54--76, H2B--50--72 and 102--124, H3--15--37 and 73--95, H4--5--27 or 6--28 and 32--54 or 42--64. According to the known experimental data on the secondary structure of histones only the following localizations are possible: H1--90--112, H2A--54--76, H2B--50--72, H3--73--95, H4--42--64. Using the known experimental data on DNA-histone interactions it is possible to suggest that these localizations of structures alpha-helix--turn--alpha-helix possible in histones H2A, H2B and H4 allows them to participate in close or structurally essential interactions of histones with DNA. The role of the predicted structure in nucleosome formation and in the autoregulation of histone biosynthesis is discussed.
DNA↗
Formation and metabolism of histone mRNAs with mutant 3' ends formed by snRNA termination signals.
Histone mRNAs are the only non-polyadenylated mRNAs, ending in a conserved 26 nt sequence which can form a stem-loop. It has not been possible to make histone mRNAs with mutant stem-loops since most mutations in the stem-loop interfere with the 3' processing reaction. The snRNA genes transcribed by RNA polymerase II form their 3' ends by transcription termination directed by a signal which is located entirely 3' of the snRNA coding sequence. Chimeric genes which express RNAs ending in a histone 3' end or in mutant histone 3' ends formed by snRNA termination signals were constructed. The mRNAs from these genes were efficiently transported from the nucleus after injection of the genes into frog oocytes. This was true even for RNAs which end in mutant stem-loops suggesting that the snRNA termination signals promote transport of the transcripts.
Animals↗
Hemimethylation of DNA prevents chromatin expression.
The activity of hemimethylated herpes simplex virus thymidine kinase DNA and chromatin was analyzed by microinjection and thymidine incorporation into the DNA of thymidine kinase-negative Rat2 cells. Hemimethylated DNA was obtained by in vitro replication of single-stranded M13 DNA constructs and of chromatin produced by in vitro reconstitution of the DNA with purified chicken histone octamers. We found that methylation of either the coding or the noncoding DNA strand was sufficient to block expression of the hemimethylated chromatin. In contrast, the hemimethylated DNA was as active as the unmethylated control DNA after microinjection until chromatin formation occurred in the recipient cells. Microinjection of chromatin hemimethylated by bacterial Hae III methyltransferase excluded the possibility that inactivation was caused by symmetrical methylation of the injected molecules.
Animals↗
cDNA sequence and expression of an intron-containing histone H2A gene from Norway spruce, Picea abies.
We have isolated a cDNA clone corresponding to a histone H2A gene from Norway spruce, Picea abies (L.) Karst. The clone was isolated on the basis of the preferential expression of the corresponding gene during germination. The identification of the clone was based on the high degree of nucleotide sequence identity (60-65%) to a range of eukaryotic histone H2A genes and the presence of a 9 amino acids long sequence identical to the conserved 'H2A box' in the deduced amino acid sequence. Like other plant histone genes, the spruce histone H2A gene encodes a polyadenylated transcript. Further, the spruce gene contains an intervening sequence of 891 bp in the coding region. The presence of introns is typical of a distinct class of replication-independent histone genes in other eukaryotes. However, the sequence of the spruce gene and its high expression in mitotically active tissues such as the apical meristem, strongly suggests that it belongs to the class of replication-dependent histone genes. This is the first documentation of an intervening sequence in this class of histone genes and the finding implies that introns were present in the ancestral histone H2A gene before the divergence of the two classes of histone genes.
Amino Acid Sequence↗
Complete nucleotide sequence of a chicken H2b histone gene.
The complete nucleotide sequence of a chicken H2b histone gene has been determined along with extensive flanking sequence both 5' and 3' from the gene. This H2b gene was isolated on a lambda Charon 4A-chicken DNA recombinant in which it is closely linked to two H3 histone genes. The H2b histone gene predicts a chicken H2b histone protein sequence differing in 5 of 125 amino acids from the sequence of a calf thymus H2b histone. The gene is uninterrupted and is flanked by several consensus sequences seen in many other eucaryotic genes. In particular, unlike many other histone genes it contains a 3'-AATAAA sequence usually associated with genes coding for polyadenylated mRNA.
Amino Acid Sequence↗
The structure, organization and differential expression of the gene encoding rat heme oxygenase-2.
Overlapping phage lambda clones were utilized to determine the complete nucleotide (nt) sequence of the rat gene encoding HO-2, the major heme oxygenase isozyme in the brain. This isozyme is the constitutive cognate of HSP32 (HO-1). The 12,563-bp gene consists of five exons and four introns, the first two exons are separated by a large intron of 8429 nt. The minus strand of intron 1 contains a nested sequence of 1046 nt with 87% identity to the cDNAs encoding the mouse and human non-histone chromosomal protein, HMG-17. In addition to the coding region, the similarity includes 40 bp upstream from the putative start codon and 800 bp of 3' untranslated sequence. The HO-2 gene lacks a conventional TATA box, but a TATA-like sequence (TAACTA) is found 26 nt upstream from the major transcription start point (tsp), as determined by primer extension. Upstream of the tsp, only a glucocorticoid-response element is found. The structure of the regulatory region is consistent with the previously demonstrated refractory nature of this isozyme to common inducers of gene expression and its apparent response to developmental changes in the adrenal steroid hormone profile. HO-2 is encoded by two transcripts (approx. 1.3 and approx. 1.9 kb), the larger of which is translated less efficiently than the smaller. Presently, we show that the transcripts are the products of a single gene and differ in the use of the polyadenylation signal.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Native genomic blotting: high-resolution mapping of DNase I-hypersensitive sites and protein-DNA interactions.
DNase I-hypersensitive sites are observed in the promoter regions of actively expressed genes, potentially active genes, and genes that were once active. We have developed an approach that greatly increases the resolution for mapping these sites by electrophoresing genomic DNA on native polyacrylamide gels prior to electroblotting and hybridization. This improved method has been used to scan the promoter and coding region of a cell-cycle-dependent human histone H4 gene with an accuracy of +/-5-10 base pairs. Protein-DNA interactions can be seen in the autoradiograph as light areas and DNase I-hypersensitive sites as dark bands. Therefore, this method provides a rapid and relatively simple means to accurately localize protein-DNA interactions as well as DNase I-hypersensitive sites, thus directly displaying DNase I hypersensitivity and protein-DNA complexes on one autoradiograph. It also potentially allows the analysis of small changes in DNase I-hypersensitive sites under various biological conditions. With this technique rather large regions of DNA can be screened to determine areas that should be analyzed by more sophisticated methods, such as genomic sequencing or gel retardation assays.
DNA, Neoplasm↗
Epigenetic alterations induced by ionizing radiation: pathways to cancer and prognostic strategies.
PURPOSE: Ionizing radiation (IR) is widely used not only in cancer diagnosis and therapy, but its biological effects also extend beyond radiation-induced lethal lesions, e.g., specifically DNA double-strand breaks (DNA-DSBs). This review aims to summarize current evidence on IR-induced epigenetic alterations and to integrate mechanistic insights from radiation chemistry and radiation biology that link DNA damage to long-term epigenetic dysregulation. RESULTS: Experimental and clinical studies collectively show that IR induces persistent epigenetic reprogramming, including global and gene-specific DNA methylation changes, radiation-responsive histone modifications, chromatin remodeling, and dysregulation of non-coding RNAs. Aberrant RNA methylation, including modifications like N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanine (m7G), and N3-methylcytosine (m3C), is closely linked to tumorigenesis and progression. Due to its tumor-specific properties, RNA methylation markers, specifically m6A, m5C, m1A, m7G, and m3C, emerge as valuable markers in liquid biopsy. Radiation chemistry studies indicate that epigenetically modified bases, for example, m5C, are preferential targets of radiation-induced oxidative damage, thereby promoting mutational hotspots and genomic instability. By altering DNA repair, apoptosis, immune responses, and cellular differentiation, these epigenetic changes promote carcinogenesis, radioresistance, and tissue toxicity. CONCLUSION: IR-induced epigenetic alterations represent a critical interface between initial DNA damage and long-term biological outcomes. Improved understanding of radiation-associated epigenetic signatures may enhance risk assessment, inform prognostic stratification, and support the development of epigenetic-targeted strategies to optimize radiotherapy and reduce adverse effects.
Ionizing radiation↗
The Mos pathway regulates cytoplasmic polyadenylation in Xenopus oocytes.
Cytoplasmic polyadenylation controls the translation of several maternal mRNAs during Xenopus oocyte maturation and requires two sequences in the 3' untranslated region (UTR), the U-rich cytoplasmic polyadenylation element (CPE), and the hexanucleotide AAUAAA. c-mos mRNA is polyadenylated and translated soon after the induction of maturation, and this protein kinase is necessary for a kinase cascade culminating in cdc2 kinase (MPF) activation. Other mRNAs are polyadenylated later, around the time of cdc2 kinase activation. To determine whether there is a hierarchy in the cytoplasmic polyadenylation of maternal mRNAs, we ablated c-mos mRNA with an antisense oligonucleotide. This prevented histone B4 and cyclin A1 and B1 mRNA polyadenylation, indicating that the polyadenylation of these mRNAs is Mos dependent. To investigate a possible role of cdc2 kinase in this process, cyclin B was injected into oocytes lacking c-mos mRNA. cdc2 kinase was activated, but mitogen-activated protein kinase was not. However, polyadenylation of cyclin B1 and histone B4 mRNA was still observed. This demonstrates that cdc2 kinase can induce cytoplasmic polyadenylation in the absence of Mos. Our data further indicate that although phosphorylation of the CPE binding protein may be involved in the induction of Mos-dependent polyadenylation, it is not required for Mos-independent polyadenylation. We characterized the elements conferring Mos dependence (Mos response elements) in the histone B4 and cyclin B1 mRNAs by mutational analysis. For histone B4 mRNA, the Mos response elements were in the coding region or 5' UTR. For cyclin B1 mRNA, the main Mos response element was a CPE that overlaps with the AAUAAA hexanucleotide. This indicates that the position of the CPE can have a profound influence on the timing of cytoplasmic polyadenylation.
Animals↗
Human La protein: a stabilizer of histone mRNA.
Histone mRNA is destabilized at the end of S phase and in cell-free mRNA decay reaction mixtures supplemented with histone proteins, indicating that histones might autoregulate the histone mRNA half-life. Histone mRNA destabilization in vitro requires three components: polysomes, histones, and postpolysomal supernatant (S130). Polysomes are the source of the mRNA and mRNA-degrading enzymes. To investigate the role of the S130 in autoregulation, crude S130 was fractionated by histone-agarose affinity chromatography. Two separate activities affecting the histone mRNA half-life were detected. The histone-agarose-bound fraction contained a histone mRNA destabilizer that was activated by histone proteins; the unbound fraction contained a histone mRNA stabilizer. Further chromatographic fractionation of unbound material revealed only a single protein stabilizer, which was purified to homogeneity, partially sequenced, and found to be La, a well-characterized RNA-binding protein. When purified La was added to reaction mixtures containing polysomes, a histone mRNA decay intermediate was stabilized. This intermediate corresponded to histone mRNA lacking 12 nucleotides from its 3' end and containing an intact coding region. Anti-La antibody blocked the stabilization effect. La had little or no effect on several other cell cycle-regulated mRNAs. We suggest that La prolongs the histone mRNA half-life during S phase and thereby increases histone protein production.
Adenosine Triphosphatases↗
Histone Sequence Database: a compilation of highly-conserved nucleoprotein sequences.
By searching the current protein sequence databases using sequences from human and chicken histones H1/H5, H2A, H2B, H3 and H4, a database of aligned histone protein sequences with statistically significant sequence similarity to the search sequence was constructed. In addition, a nucleotide sequence database of the corresponding coding regions for these proteins has been assembled. The region of each of the core histones containing the histone fold motif is identified in the protein alignments. The database contains >1300 protein and nucleotide sequences. All sequences and alignments in this database are available through the World Wide Web at http://www.ncbi.nlm.nih.gov/Baxevani/HISTO NES.
Amino Acid Sequence↗
Polyadenylated H3 histone transcripts and H3 histone variants in alfalfa.
Histone H3 mRNAs were found in polyA(+) fractions of total RNA prepared from alfalfa plants, calli and somatic embryos. The sequence analysis of cDNAs revealed the presence of a polyA tail on independent alfalfa H3 mRNAs. A highly conserved sequence motif AAUGAAA identified about 20bp upstream from the 3' ends of the alfalfa H3 cDNAs was suggested to be one of the possible regulatory elements in the 3' end formation and polyadenylation. Three out of the four analysed H3 cDNAs have more than 97% homology with a genomic clone and encode the same protein. While the fourth represents a minor species with only 78.8% homology to the coding region of the genomic clone and encodes a H3 histone with four amino acid replacements. On the basis of compilation analysis we suggest a consensus sequence for plant H3 histones which differs from that of animal's by four amino acid changes.
Amino Acid Sequence↗
Selective expression of specific histone H4 genes reflects distinctions in transcription factor interactions with divergent H4 promoter elements.
Expression of many histone H4 genes is stringently controlled during the cell cycle to maintain a functional coupling of histone biosynthesis with DNA replication. The histone H4 multigene family provides a paradigm for understanding cell cycle control of gene transcription. All functional histone H4 gene copies are highly conserved in the mRNA coding region. However, the putative promoter regions of these H4 genes are divergent. We analyzed three representative mouse H4 genes to assess whether variation in H4 promoter sequences has functional consequences for the relative level and temporal control of expression of distinct H4 genes. Using S1 nuclease protection assays with gene-specific probes and RNA from synchronized cells, we show that the mRNA level of each H4 gene is temporally coupled to DNA synthesis. However, there are differences in the relative mRNA levels of these three H4 gene copies in several cell types. Based on gel shift assays, nucleotide variations in the promoters of these H4 genes preclude or reduce binding of several histone gene transcription factors, including IRF2, HiNF-D, SP-1 and/or YY1. Therefore, differential regulation of H4 genes is directly attributable to evolutionary divergence in H4 promoter organization which dictates the potential for regulatory interactions with cognate H4 transcription factors. This regulatory flexibility in H4 promoter organization may maximize options for transcriptional control of histone H4 gene expression in response to the onset of DNA synthesis and cell cycle progression in a broad spectrum of cell types and developmental stages.
3T3 Cells↗
Inhibition of transcription does not affect the total amount of ubiquitinated histone 2A in chromatin.
Using a polyclonal anti-ubiquitin antibody in Western blotting experiments, we detected three antibody-binding components in a HeLa cell extract: ubiquitin, a ubiquitin-histone 2A conjugate (uH2A) and a 17 kD protein, probably corresponding to an additional ubiquitin conjugate. Since ubiquitination of histone 2A (H2A) has been invoked in the transcription process, the amount of uH2A was studied after inhibition of ribosomal RNA (rRNA) synthesis with actinomycin D and of heterogeneous nuclear RNA (hnRNA) synthesis with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). The amount of uH2A did not change, suggesting that the overall level of ubiquitination of histone 2A is not directly coupled to on-going transcription of either rRNA or hnRNA. Since the uH2A content of protein coding genes constitutes a considerable portion of total chromatin uH2A, it seems also likely that there is no major change in the degree of ubiquitination on the templates of the protein-coding genes themselves upon cessation of transcription. It is proposed that the pattern of ubiquitination of histone 2A is established on a long-term basis and that it is related to the overall organization and distribution of the chromatin material in the interphase nucleus.
Chromatin↗