Making proteins in higher cells.
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Animals↗
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Results for “Histone Code”
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Cyclic AMP in metabolism.
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Adenine Nucleotides↗
Genomic clones coding for some of the initial genes expressed during Drosophila development.
Preblastoderm Drosophila embryos were made permeable and labeled in vivo with [32P]phosphate-containing medium. Cytoplasmic polyadenylylated RNA was extracted from these embryos and used to screen a library of Drosophila genomic DNA sequences cloned in phage lambda. Ten cloned sequences were selected for further study. These sequences were not complementary to mitochondrial DNA, nor did they contain the repeated nuclear genes coding for rRNA or histones. The cloned sequences each encode one or more unique genes expressed in preblastoderm embryos. RNA blot analysis indicated that some of these genes are also expressed at other times during embryogenesis. These results show that, in spite of the rapid nuclear divisions taking place during the preblastoderm stage, Drosophila nuclear genes are transcribed and that a subset of these genes show variable, stage-specific levels of expression during early embryogenesis.
Animals↗
Silent nucleotide substitutions and the molecular evolutionary clock.
Half of the nucleotide substitutions during the evolutionary divergence of genes in animals, bacteria, and viruses are silent changes. These result from an inherent biochemical property of DNA and are fixed by genetic drift. Evolution may be viewed as a device for protecting DNA molecules from extinction.
Animals↗
Proteins present in bovine papillomavirus particles.
Analysis by two-dimensional gel electrophoresis and silver staining of heavy full, light full, and empty bovine papillomavirus particles has shown that the major capsid protein L1 is highly modified. Besides exhibiting at least 13 isoelectric point variants of approximately the same molecular mass (54 kilodaltons), it is suggested that an additional heavier protein chain (69 kilodaltons) is also derived from L1 by glycosylation. These modifications may stabilize the particle structure. Treatment with neuraminidase reduces the number of modification products detectable, with a concomitant increase in the more basic forms of L1. Although it was not possible to detect histones in any of the preparations, proteins of similar molecular mass were detected. Therefore, it is suggested that the basic tails of L1 bind to the DNA in a manner similar to that of histone. Calculation of the theoretical mobilities of the papillomavirus proteins shows good agreement with the actual position of L1 and its isoelectric point variants and suggests that two of the proteins with molecular masses similar to those of the histones may actually be coded by the bovine papillomavirus E7 and E5 open reading frames.
Animals↗
Aspects of molecular evolution.
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Alleles↗
m6A RNA modification and its emerging roles in diseases: recent advances and therapeutic implications.
BACKGROUND: In the recent past, insights in post transcriptional regulation of gene expression have profoundly reshaped our understanding of the molecular mechanisms underlying health and disease. This paradigm shift largely stems from the emerging field of epitranscriptomics, which highlights the pivotal role of chemical RNA modifications. While more than 170 distinct chemical modifications on the RNA are known, the m6A modification is the most abundant internal mRNA modification in higher eukaryotic cells, present not only on protein coding transcripts but also on non-coding RNAs, regulated by “writers”, “erasers”, and “readers” that together modulate alternative splicing, nuclear export, translation efficiency, and mRNA stability. MAIN BODY: This review addresses an important gap by presenting a multilayered regulatory framework that catalogs the full repertoire of m6A machinery and uniquely reveals how non-coding RNAs, transcription factors, histone modifications, and chromatin remodelers governs the spatiotemporal specificity of m6A modification. We explore how dysregulation of m6A modification and its regulatory proteins contribute to the development and progression of various diseases such as cardiovascular disease, neurological disorders, cancer, and type 2 diabetes through context-dependent modulation of gene networks. Furthermore, we present an integrative overview of the therapeutic pipeline, tracing the development of small-molecule inhibitors targeting m6A regulators, thus bridging a crucial link between fundamental mechanisms and new therapies. CONCLUSIONS: Overall, this review integrates current findings and emerging insights to provide a comprehensive understanding of m6A biology. By linking upstream regulatory mechanisms with downstream pathological consequences and therapeutic interventions, we highlight the potential of targeting the epitranscriptome for clinical applications.
Humans↗
Genes in multiple copies as the primary cause of aging.
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9,10-Dimethyl-1,2-benzanthracene↗
[A model of error theory as a molecular interpretation of aging].
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Aging↗
Chromatin structure of histone genes in sea urchin sperms and embryos.
The nucleosomal organization of active and repressed alpha subtype histone genes has been investigated by micrococcal nuclease digestion of P. lividus sperm, 32-64 cell embryo and mesenchyme blastula nuclei, followed by hybridization with 32P-labeled specific DNA probes. In sperms, fully repressed histone genes are regularly folded in nucleosomes, and exhibit a greater resistance to micrococcal nuclease cleavage than bulk chromatin. In contrast, both coding and spacer alpha subtype histone DNA sequences acquire an altered conformation in nuclei from early cleavage stage embryos, i.e., when these genes are maximally expressed. Switching off of the alpha subtype histone genes, in mesenchyme blastulae, restores the typical nucleosomal organization on this chromatin region. As probed by hybridization to D.melanogaster actin cDNA, actin genes retain a regular nucleosomal structure in all the investigated stages.
Animals↗
Isolation and characterization of two human H1 histone genes within clusters of core histone genes.
Two human H1 histone genes, termed H1.3 and H1.4, were isolated from two cosmid clones. The H1.4 gene is associated with an H2B gene, whereas genes coding for all four core histones are located in the vicinity of the H1.3 gene. This cluster arrangement was found both in the two cosmid clones and on overlapping bacteriophage clones isolated from an EMBL3 library. In continuation of our previous analysis of two human H1 genes, this analysis raises the number of completely sequenced H1 histone genes within clusters of core histone genes to four.
Amino Acid Sequence↗
Transcription unit of the chicken histone H5 gene and mapping of H5 pre-mRNA sequences.
We have analyzed the transcription unit of the gene coding for the erythrocyte-specific histone H5. RNA transcripts elongated in vitro by permeabilized immature cells hybridized to the template strand of the structural gene as well as to 3'-flanking sequences. Approximately 90% of the engaged RNA polymerase II molecules terminate transcription within a region of about 500 base pairs immediately downstream of the polyadenylation site. S1 nuclease protection experiments indicated that the downstream sequences are also transcribed in vivo, their relative amounts reflecting the distribution of RNA polymerases observed in vitro. RNA molecules extending up to 1.14 kilobase pairs downstream of the polyadenylation site were detected, but no unique site of termination was found. The sequence of the transcription termination region shows no obvious homology to those of other RNA polymerase II termination regions. The possible involvement of altered DNA and/or chromatin structures in the transcription termination process is discussed.
Animals↗
Multiple control level governing H10 mRNA and protein accumulation.
We have studied the variation of histone H10 and of its coding mRNA during rat liver regeneration after partial hepatectomy. Our data showed that while H10 decreased when cell proliferation was initiated, H10 mRNA accumulated in a proliferation-dependent manner as did H3 mRNA. These results showed two interesting aspects of the regulation of H10 expression in vivo, confirming results we have obtained previously in vitro: first H10 mRNA accumulation is a proliferation-dependent event; second, H10 protein accumulation may be uncoupled from that of its coding mRNA.
Animals↗
Cytoskeletal neurofilament gene expression in brain tissue from Alzheimer's disease patients. I. Decrease in NF-L and NF-M message.
The cytoskeletal changes seen in brains of patients with Alzheimer's disease include neurofibrillary tangles, neuritic plaques, Hirano bodies, and granulovacuolar degeneration. Northern and slot blot analyses were used to investigate the expression of the genes coding for actin, tubulin, neurofilaments, and histone in brain tissue from Alzheimer's disease patients and normal aged controls. We found a marked decrease of 94% in the expression of the neurofilament gene coding for the medium size subunit (150 kDa) and a 73% decrease in the expression of the gene coding for the small subunit (68 kDa) in Alzheimer's disease patients as compared to controls. Expression of the other genes, such as actin and histone, did not show any significant difference. Expression of the gene coding for medium size, neurofilament gene was not decreased in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease. This abnormality in neurofilament gene expression may explain some of the pathologic features found in Alzheimer's disease patients.
Aged↗
Involvement of the 5'-leader sequence in coupling the stability of a human H3 histone mRNA with DNA replication.
Two lines of evidence derived from fusion gene constructs indicate that sequences residing in the 5'-nontranslated region of a cell cycle-dependent human H3 histone mRNA are involved in the selective destabilization that occurs when DNA synthesis is terminated. The experimental approach was to construct chimeric genes in which fragments of the mRNA coding regions of the H3 histone gene were fused with fragments of genes not expressed in a cell cycle-dependent manner. After transfection in HeLa S3 cells with the recombinant plasmids, levels of fusion mRNAs were determined by S1 nuclease analysis prior to and following DNA synthesis inhibition. When the first 20 nucleotides of an H3 histone mRNA leader were replaced with 89 nucleotides of the leader from a Drosophila heat-shock (hsp70) mRNA, the fusion transcript remained stable during inhibition of DNA synthesis, in contrast to the rapid destabilization of the endogenous histone mRNA in these cells. In a reciprocal experiment, a histone-globin fusion gene was constructed that produced a transcript with the initial 20 nucleotides of the H3 histone mRNA substituted for the human beta-globin mRNA leader. In HeLa cells treated with inhibitors of DNA synthesis and/or protein synthesis, cellular levels of this histone-globin fusion mRNA appeared to be regulated in a manner similar to endogenous histone mRNA levels. These results suggest that the first 20 nucleotides of the leader are sufficient to couple histone mRNA stability with DNA replication.
Animals↗
Histone H1 expressed in Saccharomyces cerevisiae binds to chromatin and affects survival, growth, transcription, and plasmid stability but does not change nucleosomal spacing.
Histone H1 is proposed to serve a structural role in nucleosomes and chromatin fibers, to affect the spacing of nucleosomes, and to act as a general repressor of transcription. To test these hypotheses, a gene coding for a sea urchin histone H1 was expressed from the inducible GAL1 promoter in Saccharomyces cerevisiae by use of a YEp vector for high expression levels (strain YCL7) and a centromere vector for low expression levels (strain YCL1). The H1 protein was identified by its inducibility in galactose, its apparent molecular weight, and its solubility in 5% perchloric acid. When YCL7 was shifted from glucose to galactose for more than 40 h to achieve maximal levels of H1, H1 could be copurified in approximately stoichiometric amounts with core histones of Nonidet P-40-washed nuclei and with soluble chromatin fractionated on sucrose gradients. While S. cerevisiae tolerated the expression of low levels of H1 in YCL1 without an obvious phenotype, the expression of high levels of H1 correlated with greatly reduced survival, inhibition of growth, and increased plasmid loss but no obvious change in the nucleosomal repeat length. After an initial induction, RNA levels for GAL1 and H1 were drastically reduced, suggesting that H1 acts by the repression of galactose-induced genes. Similar effects, but to a lower extent, were observed when the C-terminal tail of H1 was expressed.
Animals↗
The Leishmania infantum histone H3 possesses an extremely divergent N-terminal domain.
The isolation of a Leishmania cDNA clone coding for an antigen identified as the histone H3 is described. The nucleotide sequence of the cDNA predicts that the Leishmania histone H3 contains 129 residues and that it has a molecular mass of 14,620 Da. Comparison of the amino acid sequence with the consensus sequence of the eukaryotic histone H3 shows that the Leishmania protein has a highly conserved globular region and an extremely divergent amino-terminal portion.
Amino Acid Sequence↗
The human replacement histone H3.3B gene (H3F3B).
H3.3 is a replacement histone subtype that is encoded by two replication-independent genes termed H3.3A and H3.3B, respectively. We have isolated a fullsize H3.3 cDNA clone from an oligo(dT)-primed human testicular cDNA library. Subsequently, the corresponding gene was isolated from a human cosmid library and was identified as the H3.3B gene. It was the only histone gene on this 42-kb cosmid clone. The gene structure shows characteristic features of an H3.3 gene. First, it contains an intron of about 0.5 kb in the 5' untranslated region and two smaller introns within the coding gene portion. Second, no histone gene-specific dyad symmetry element was found in the 3' untranslated region, but three putative polyadenylation signals were detected downstream of the gene. The corresponding transcripts were detected by Northern blot analysis using poly(A)+ RNA from testis and from the HEK293 tumor cell line. The newly discovered human H3.3B gene (HGMW-approved symbol H3F3B) was mapped by fluorescence in situ hybridization to the telomeric region of chromosome 17 (17q25). This localization of the H3.3B gene and its solitary arrangement contrast with the majority of the replication-dependent histone genes, which form a large cluster on chromosome 6 and a second cluster on chromosome 1.
Amino Acid Sequence↗