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PubMed1978

Histone genes in macronuclear DNA of the ciliate Stylonychia mytilus.

DNA in the macronucleus of Stylonychia mytilus exists as discrete gene-sized fragments which are derived from micronuclear DNA through a series of well-defined developmental events. It has been proposed that each of the DNA fragments might represent a gene and its controlling elements. We have investigated this possibility using genes which code for the five histone proteins. Macronuclear DNA fragments were fractionated according to size by agarose gel electrophoresis, the fragments transferred to nitrocellulose filters using the technique of Southern, and the filter-bound DNA hybridized with labeled cloned histone genes of the sea urchin, Psammechinus miliaris. Results indicate, first, that sequences homologous to the five individual histone gene probes are present in discrete macronuclear fragments which appear as bands in the gel hybridization assay. Secondly, for each of the five individual histone gene probes the homologous DNA fragments are several in number, ranging in size in from 7.6 Kb (Kilo base pairs) to 0.73 Kb. For example, the largest of six detected fragments hybridizing to the H3 gene probe contains approximately 10 times the amount of DNA required to code for a Stylonychia H3 histone. The smallest detected fragment hybridizing to the H3 probe contains enought DNA to code for approximately two copies of the histone. Finally, in general, no two histone approximately two copies of the histone. Finally, in general, no two histone gene probes hybridized to the same macronuclear DNA fragment. This result indicates that genes coding for the five histones in Stylonychia are not located together on the same macronuclear DNA fragments and implies that the five functionally related genes would not be transcribed together as a polycistronic unit.

Animals↗
PubMed1990

The two macronuclear histone H4 genes of the hypotrichous ciliate Stylonychia lemnae.

Macronuclear DNA of hypotrichous ciliates is organized in short gene-sized molecules, each containing all regulatory sequences for autonomous replication and expression. In these organisms the histone genes are not clustered but dispersed on different molecules of various sizes. Two histone H4 genes containing fragments, one of 1.7 kb and one of 2.8 kb, were found in the macronucleus of Stylonychia lemnae. Restriction and sequence data reveal that the two genes-sized pieces are derived from different micronuclear precursors. Both histone H4 genes code for the same protein of 103 aminoacids but differ greatly in their 5'-and 3'-regions.

Amino Acid Sequence↗
PubMed1978

Genes and spacers of cloned sea urchin histone DNA analyzed by sequencing.

A cloned histone gene cluster of the highly reiterated type from the sea urchin Psammechinus miliaris was analyzed by DNA sequencing. More than half of the 6 kb repeat was sequenced, including coding regions of all five histones, some prelude and trailing sequences lying adjacent to the structural gense, and segments of the AT-rich spacer DNA. The gene cluster does not code for gonad-specific histone variants but may instead be active in early sea urchin development, as indicated by comparison to reference histones. The encoded histones seem not to be derived from longer precursor proteins, not is there any evidence for insert sequences within the coding regions. Sequence similarities exist among the putative ribosome-binding sites adjacent to the initiator codons of individual genes. The AT-rich spacer segments between the genes differ from each other, are made up from relatively simple nucleotide arrangements, but are not repetitious, and apparently do not code for additional large proteins.

Animals↗
PubMed1979

Isolation of a genomal clone containing chicken histone genes.

We have used enriched chicken histone cDNA to select genomal clones from a chicken library. Because the cDNA probe also contained other sequences, a further screening of positive plagues with negative probes eliminated most non-histone gene clones. One 'positively-selected' genomal clone, lambda CH-01, hybridised with cloned sea-urchin histone genes and also detected histone genes in EcoRI-digested genomal sea-urchin DNA. Limited DNA sequencing of HaeIII fragments identified two sequences within the coding region of chicken histone H2A. A third fragment predicted an amino acid sequence with strong homology to an H1 histone sequence.

Amino Acid Sequence↗
PubMed1990

Coding and noncoding sequences at the 3' end of yeast histone H2B mRNA confer cell cycle regulation.

Yeast (Saccharomyces cerevisiae) histone mRNA synthesis is tightly regulated to the S phase of the cell division cycle as a result of both transcriptional and posttranscriptional regulation. We focused on the role of posttranscriptional control in histone H2B1 gene (HTB1) regulation and studied a portion of the HTB1 message required for cell-cycle-specific accumulation. The 3' end of the HTB1 gene containing a 17-amino-acid coding sequence and entire noncoding sequence was fused to the bacterial neomycin phosphotransferase II gene (neo) under control of the GAL1 promoter. The expression of the endogenous and chimeric HTB1 genes was analyzed during the yeast cell cycle. As yeast cells entered a synchronous cell cycle following release from alpha-factor arrest, the level of GAL1-promoter-controlled neo-HTB1 message increased approximately 12-fold during S phase and dropped to basal level when the cells left S phase. This indicates that the 3' end of the HTB1 mRNA is capable of conferring cycle-specific regulation on a heterologous message. Deletion analysis of the 3' end showed that the signal for cell cycle control of HTB1 mRNA includes contiguous coding and noncoding sequences surrounding the stop codon. This differs from the situation in mammalian cells, whose posttranscriptional regulation of histone genes is mediated through a short sequence containing a stem-loop structure near the very terminus of the untranslated 3' end.

Base Sequence↗
PubMed1990

A cytotoxic monoclonal anti-leukemia antibody binds to histone H1.

Monoclonal antibody (MAb) AP64 is a mouse IgM MAb raised against human acute non-lymphocytic leukemia (ANLL) cells. It has been shown to bind to a wide variety of cell lines and is capable of initiating complement (C) dependent cytotoxicity. Other studies indicated that MAb AP64 can effect long term cure in a leukemia minimal residual disease model. By using various techniques we have determined the identity of a protein which is bound by this MAb. Immunofluorescent studies have shown that MAb AP64 stains the nuclei of fixed cells as well as metaphase chromosomes, indicating that this MAb binds to a component of chromatin. Biochemical characterization revealed that MAb AP64 western blots a 31 and 32 kilodalton doublet from NP-40 extracts from both rat and human leukemia cells. The mobility of this doublet is identical under reducing and non-reducing conditions. Further studies have shown that the bands detected by western blot analysis using MAb AP64 as a probe have a similar migration to those of bovine histone H1. Also, 1 nanogram of bovine histone H1 can be detected by MAb AP64 when spotted onto nitrocellulose. These data demonstrate that MAb AP64 binds to a conserved epitope present on molecules coded for by the histone H1 gene family.

Antibodies, Monoclonal↗
PubMedDate not supplied

Non-coding DNA in macronuclear chromosomes of hypotrichous ciliates.

Massive elimination of sequences occurs in the development of the macronucleus of hypotrichous ciliates. The surviving sequences are presumed to have functions in the macronucleus; what little is known about non-coding macronuclear sequences is reviewed. The 1.7 kbp macronuclear chromosome that carries a histone H4 gene consists primarily of non-coding DNA 5' of the histone gene. This region is shown by sequence comparison to carry several perfectly conserved sequence blocks up to 14 bp long, scattered amongst regions which have evolved greatly since the divergence of Oxytricha nova and Stylonychia lemnae. This result is consistent with the suggestion of Harper and Jahn [Harper, D. S. & Jahn, C. L. 1989. Actin, tubulin and H4 histone genes in three species of hypotrichous ciliated protozoa. Gene, 75:93-107] that this large non-coding 5' region may be involved in the transcriptional regulation of the histone H4 gene carried on the 1.7 kbp chromosome. Very little is known about transcriptional control in hypotrichs; identification of conserved non-coding sequences of orthologous hypotrich genes promises to provide clues to potential cis-acting control signals.

Animals↗
PubMed1978

Hatching in the sea urchin Lytechinus pictus is accompanied by a shift in histone H4 gene activity.

There is a distinct shift in histone mRNA synthesis at approximately 11--12 hr of sea urchin emhryogenesis, coincident with embryonic hatching. The synthesis of the blastula type (early) histone mRNAs gradually ceases at this stage and a new class of posthatching (late) histone mRNAs is produced. Briefly labeled early and late mRNAs were isolated and identified by means of RNA-DNA hybridization to different cloned histone genes. The late histone HI mRNA is approximately 40 nucleotides longer than the early HI mRNA. The H3, H2A, H2B, and H4 late mRNAs are 15--40 nucleotides shorter than their early counterparts. We present sequence evidence to show that the genes coding for the late H4 mRNA are a separate class from those that code for the early histone H4 message.

Animals↗
PubMed1991

The histone H1-lacZ' fusion protein produced in Escherichia coli binds to the 5'-TTGGCAnnnTGCCAA-3' motif on DNA.

The coding region of the chicken histone H1.03 gene was cloned to a bacterial expression vector, and the 291-amino acid H1-beta-galactosidase fusion protein was isolated after induction with IPTG. The fusion protein recognizes the 5'-TTGGCAnnnTGCCAA-3' motif on DNA. The H1 globular domain was initially shown to be responsible for the sequence-specific binding by functional deletion analysis. This function may be indispensable for the role of H1 as a determinant of nucleosome positioning and as a eukaryotic repressor.

Animals↗
PubMed1992

Nuclear matrix proteins bind very tightly to specific regions of the chicken histone H5 gene.

The nuclear matrix is operationally defined as the structure remaining after nuclease-digested nuclei are extracted with high concentrations of salt. The nuclear matrix is thought to have a role in organizing higher order chromatin into loop domains. We determined whether specific regions of the histone H5 gene were very tightly bound to protein of erythrocyte and liver nuclear matrices in vitro. We demonstrate that DNA fragments spanning sequences 5' to the promoter and the 3' enhancer region of the histone H5 gene, but not DNA fragments spanning the promoter, were very tightly bound to protein of nuclear matrices of erythrocytes and liver. The nuclear matrix consists of internal nuclear matrix and nuclear pore-lamina complex. Recently, we demonstrated that histone deacetylase could be used as a marker enzyme of the internal nuclear matrix. We demonstrate that nuclear pore-lamina complex preparations that were depleted of histone deacetylase activity, and thus of internal nuclear matrix, retained the protein that bound very tightly to the beta-globin and histone H5 enhancers. These results provide evidence that specific regions of the histone H5 gene are very tightly bound to nuclear pore-lamina complex protein.

Animals↗
PubMed2026

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1977

Application of the avidin-biotin method of gene enrichment to the isolation of long double-stranded DNA containing specific gene sequences.

A method of enriching for long double-stranded segments of eukaryotic DNA carrying particular genes is described. A purified RNA coded for by the gene is covalently attached to biotin via the protein, cytochrome c. This modified RNA is hybridized to total nuclear, double-stranded DNA under conditions that allow the formation of R-loops. Avidin, which has a high affinity for biotin, is covalently attached to polymer spheres. The complexes of avidin-spheres with DNA:RNA-biotin R-loop hybrids band in CsCl at a much lower bouyant density than does free DNA. This density is a function of the length of DNA coupled per avidin-sphere. This method was used to prepare very long double-strands of DNA highly enriched in the coding sequences for the large rRNAs of D. melanogaster and L. donovani and the histone mRNAs of S. purpuratus.

Animals↗
PubMed1992

Code domains in tandem repetitive DNA sequence structures.

Traditionally, many people doing research in molecular biology attribute coding properties to a given DNA sequence if this sequence contains an open reading frame for translation into a sequence of amino acids. This protein coding capability of DNA was detected about 30 years ago. The underlying genetic code is highly conserved and present in every biological species studied so far. Today, it is obvious that DNA has a much larger coding potential for other important tasks. Apart from coding for specific RNA molecules such as rRNA, snRNA and tRNA molecules, specific structural and sequence patterns of the DNA chain itself express distinct codes for the regulation and expression of its genetic activity. A chromatin code has been defined for phasing of the histone-octamer protein complex in the nucleosome. A translation frame code has been shown to exist that determines correct triplet counting at the ribosome during protein synthesis. A loop code seems to organize the single stranded interaction of the nascent RNA chain with proteins during the splicing process, and a splicing code phases successive 5' and 3' splicing sites. Most of these DNA codes are not exclusively based on the primary DNA sequence itself, but also seem to include specific features of the corresponding higher order structures. Based on the view that these various DNA codes are genetically instructive for specific molecular interactions or processes, important in the nucleus during interphase and during cell division, the coding capability of tandem repetitive DNA sequences has recently been reconsidered.

Animals↗