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At least 919 records · Page 51Linked to original sources
PubMed1996

Binding of nuclear proteins to a conserved histone H1t promoter element suggests an important role in testis-specific transcription.

The testis-specific histone H1t gene is transcribed only in primary spermatocytes during spermatogenesis. Recently, expression of the rat gene was shown to be limited to primary spermatocytes in transgenic mice, revealing that promoter elements sufficient for regulating tissue-specific transcription were present in the cloned rat gene. In this study the mouse histone H1t gene has been cloned, and sequenced and its promoter region has been compared to the rat H1t promoter with regard to conserved elements and protein binding activity. The amino acid sequence of each of the three H1t coding region domains is conserved when compared to the homologous domain in H1t derived from other species. H1t mRNA is found only in testis, where it accumulates to a high steady-state level, and examination of enriched testis cell populations shows that expression is limited to primary spermatocytes. Protein binding assays using nuclear extracts from various mouse tissues reveal testis-specific binding to TE1 and TE2, imperfect inverted repeat elements within the larger TE element. Although the H1t promoter contains an Sp1 consensus motif within the H1t/TE element, binding of testis Sp1 to the motif could not be detected using specific anti-Sp1 antibodies.

Amino Acid Sequence↗
PubMed2006

Individual subunits of the Ssn6-Tup11/12 corepressor are selectively required for repression of different target genes.

The Saccharomyces cerevisiae Ssn6 and Tup1 proteins form a corepressor complex that is recruited to target genes by DNA-bound repressor proteins. Repression occurs via several mechanisms, including interaction with hypoacetylated N termini of histones, recruitment of histone deacetylases (HDACs), and interactions with the RNA polymerase II holoenzyme. The distantly related fission yeast, Schizosaccharomyces pombe, has two partially redundant Tup1-like proteins that are dispensable during normal growth. In contrast, we show that Ssn6 is an essential protein in S. pombe, suggesting a function that is independent of Tup11 and Tup12. Consistently, the group of genes that requires Ssn6 for their regulation overlaps but is distinct from the group of genes that depend on Tup11 or Tup12. Global chip-on-chip analysis shows that Ssn6 is almost invariably found in the same genomic locations as Tup11 and/or Tup12. All three corepressor subunits are generally bound to genes that are selectively regulated by Ssn6 or Tup11/12, and thus, the subunit specificity is probably manifested in the context of a corepressor complex containing all three subunits. The corepressor binds to both the intergenic and coding regions of genes, but differential localization of the corepressor within genes does not appear to account for the selective dependence of target genes on the Ssn6 or Tup11/12 subunits. Ssn6, Tup11, and Tup12 are preferentially found at genomic locations at which histones are deacetylated, primarily by the Clr6 class I HDAC. Clr6 is also important for the repression of corepressor target genes. Interestingly, a subset of corepressor target genes, including direct target genes affected by Ssn6 overexpression, is associated with the function of class II (Clr3) and III (Hst4 and Sir2) HDACs.

Acetylation↗
PubMed1993

Spermidine-induced alteration in the gene-spacer discrimination of nucleases in protonated DNA.

The sequence preference of a Drosophila lysosomal DNase was studied on the Drosophila hsp 70 heat-shock and histone recombinants, which carry six different genes, and the surrounding spacer sequences. The distribution of cleavage sites was random in respect of the locations of gene and spacer sequences. However, in the presence of 10 mM spermidine, a major transition was observed: the coding sequences became more susceptible than the spacer regions to nuclease attack. A similar transition was induced in the sequence preference of DNase I if the digestion was performed in the presence of spermidine at pH 5.2. At pH 7.5, spermidine does not influence the sequence preference of DNase I, which indicates the involvement of DNA protonation in this transition. In the presence of spermidine, the distributions of preferred and protected sequences were almost indistinguishable for these nucleases, suggesting that the protonated DNA, and not the enzymes, is the target of spermidine. A Drosophila embryonal protein was detected and partially purified which induced the same transition as observed in the presence of spermidine. The purified protein preferentially protected the spacer DNA sequences against acid DNase or DNase I cleavage in the hsp 70 heat-shock and histone gene recombinants. The protection was concentration dependent and occurred only at pH 5.2. The transition of nuclease specificity is probably due to a conformational change in the protonated DNA, induced by the binding of either the embryonal protein or spermidine.

Animals↗
PubMed1988

Multiple introns in a conjugation-specific gene from Tetrahymena thermophila.

Multiple introns have been found in a gene from a ciliated protozoan. This Tetrahymena thermophila gene (cnjB) is large (7.5 kb mRNA) and active only during conjugation, the organism's sexual cycle. Six introns ranging in size from 62 bp to 676 bp were found when we sequenced a 3.1 kb segment of the cnjB gene together with its corresponding cDNA. We estimate, by extrapolation of our current data, a total of approximately 30 introns in this gene with a total gene size (introns plus exons) of 15 kb or more. The number of introns is surprising given the scarcity of introns in ciliate genes examined to date. Our findings constitute the first example of multiple introns in a ciliate gene. Having the sequence of several introns has allowed us to construct consensus sequences for T. thermophila mRNA introns. The 5' and 3' intron junctions resemble those of general nuclear mRNA (GT/AG rule is followed) but differences are seen. In particular, stretches of 10 or more adenines and thymines are found adjacent to the conserved GT and AGs at the junctions. Unusual aspects of the coding region of this gene are discussed.

Amino Acid Sequence↗
PubMed2004

The protease Lon and the RNA-binding protein Hfq reduce silencing of the Escherichia coli bgl operon by H-NS.

The histone-like nucleoid structuring protein H-NS represses the Escherichia coli bgl operon at two levels. H-NS binds upstream of the promoter, represses transcription initiation, and binds downstream within the coding region of the first gene, where it induces polarity of transcription elongation. In hns mutants, silencing of the bgl operon is completely relieved. Various screens for mutants in which silencing of bgl is reduced have yielded mutations in hns and in genes encoding the transcription factors LeuO and BglJ. In order to identify additional factors that regulate bgl, we performed a transposon mutagenesis screen for mutants in which silencing of the operon is strengthened. This screen yielded mutants with mutations in cyaA, hfq, lon, and pgi, encoding adenylate cyclase, RNA-binding protein Hfq, protease Lon, and phosphoglucose isomerase, respectively. In cyaA mutants, the cyclic AMP receptor protein-dependent promoter is presumably inactive. The specific effect of the pgi mutants on bgl is low. Interestingly, in the hfq and lon mutants, the downstream silencing of bgl by H-NS (i.e., the induction of polarity) is more efficient, while the silencing of the promoter by H-NS is unaffected. Furthermore, in an hns mutant, Hfq has no significant effect and the effect of Lon is reduced. These data provide evidence that the specific repression by H-NS can (directly or indirectly) be modulated and controlled by other pleiotropic regulators.

ATP-Dependent Proteases↗
PubMed2005

Preferential occupancy of histone variant H2AZ at inactive promoters influences local histone modifications and chromatin remodeling.

The yeast histone variant H2AZ (Htz1) is implicated in transcription activation, prevention of the ectopic spread of heterochromatin, and genome integrity. Our genome-wide localization analysis revealed that Htz1 is widely, but nonrandomly, distributed throughout the genome in an SWR1-dependent manner. We found that Htz1 is enriched in intergenic regions compared with coding regions. Its occupancy is inversely proportional to transcription rates and the enrichment of the RNA polymerase II under different growth conditions. However, Htz1 does not seem to directly regulate transcription repression genome-wide; instead, the presence of Htz1 under the inactivated condition is essential for optimal activation of a subset of genes. In addition, Htz1 is not generally responsible for nucleosome positioning, even at those promoters where Htz1 is highly enriched. Finally, using a biochemical approach, we demonstrate that incorporation of Htz1 into nucleosomes inhibits activities of histone modifiers associated with transcription, Dot1, Set2, and NuA4 and reduces the nucleosome mobilization driven by chromatin remodeling complexes. These lines of evidence collectively suggest that Htz1 may serve to mark quiescent promoters for proper activation.

Chromatin Assembly and Disassembly↗
PubMed2001

Further biochemical characterization of Mycobacterium leprae laminin-binding proteins.

It has been demonstrated that the alpha2 chain of laminin-2 present on the surface of Schwann cells is involved in the process of attachment of Mycobacterium leprae to these cells. Searching for M. leprae laminin-binding molecules, in a previous study we isolated and characterized the cationic proteins histone-like protein (Hlp) and ribosomal proteins S4 and S5 as potential adhesins involved in M. leprae-Schwann cell interaction. Hlp was shown to bind alpha2-laminins and to greatly enhance the attachment of mycobacteria to ST88-14 Schwann cells. In the present study, we investigated the laminin-binding capacity of the ribosomal proteins S4 and S5. The genes coding for these proteins were PCR amplified and their recombinant products were shown to bind alpha2-laminins in overlay assays. However, when tested in ELISA-based assays and in adhesion assays with ST88-14 cells, in contrast to Hlp, S4 and S5 failed to bind laminin and act as adhesins. The laminin-binding property and adhesin capacity of two basic host-derived proteins were also tested, and only histones, but not cytochrome c, were able to increase bacterial attachment to ST88-14 cells. Our data suggest that the alanine/lysine-rich sequences shared by Hlp and eukaryotic H1 histones might be involved in the binding of these cationic proteins to laminin.

Animals↗
PubMed2002

The absence of Mth1 inactivation and DNA polymerase kappa overexpression in rat mammary carcinomas with frequent A:T to C:G transversions.

Single nucleotide instability (SNI), an increase in spontaneous point mutation rates (MRs) without involvement of microsatellite instability, is present in rat mammary carcinoma cell lines and human breast cancer cell lines. A:T to C:G transversions, which are generally rare, were frequently observed in two rat mammary carcinoma cell lines and in their primary carcinomas, and were considered to be related to the molecular mechanism of SNI. In this study, two known molecular mechanisms that cause increases of A:T to C:G transversions, inactivation of the MutT mammalian homologue (Mth1) gene and overexpression of the DNA polymerase k (Pol k) gene, were analyzed in two rat mammary carcinoma cell lines and 11 rat primary carcinomas. PCR-SSCP analysis revealed no mutations in the entire Mth1 coding region. Quantitative real-time RT-PCR analysis showed that Mth1 mRNA expression was slightly, but significantly, increased in the primary carcinomas (P = 0.001 using GAPDH for normalization, and P = 0.002 using histone H4, t-test), contrary to our expectation, and was decreased to 1 / 2 in the cell lines. The expression of Pol k, which is known to be error-prone with frequent A:T to C:G transversions, was rather decreased in the cell lines and primary carcinomas. Inactivation of Mth1 and overexpression of Pol k were unlikely to have caused SNI in the two rat mammary carcinoma cell lines with a high frequency of A:T to C:G transversions, and searching for other unknown molecular mechanisms is important.

Animals↗
PubMed1999

Cloning and analysis of a Toxoplasma gondii histone acetyltransferase: a novel chromatin remodelling factor in Apicomplexan parasites.

The yeast transcriptional adaptor GCN5 functions as a histone acetyltransferase, directly linking chromatin modification to transcriptional regulation. Homologues of yeast GCN5 have been found in Tetrahymena, Drosophila, Arabidopsis and human, suggesting that this pathway of chromatin remodelling is evolutionarily conserved. Consistent with this view, we have identified the Toxoplasma gondii homologue, referred to here as TgGCN5. The gene codes for a protein of 474 amino acids with an estimated molecular mass of 53 kDa. The protein reveals two regions of close similarity with the GCN5 family members, the HAT domain and the bromodomain. Tg GCN5 occurs in a single copy in the T.gondii genome. The introduction of a second copy of TgGCN5 in T.gondii tachyzoites is toxic unless the HAT activity is disrupted by a single point mutation. Full TgGCN5 does not complement the growth defect in a yeast gcn5 (-)mutant strain, but a chimera comprising the T.gondii HAT domain fused to the remainder of yGCN5 does. These data show that T.gondii GNC5 is a histone acetyltransferase attesting to the significance of chromatin remodelling in gene regulation of Apicomplexa.

Acetylation↗
PubMed2001

Association of deletions and translocation of the reduced folate carrier gene with profound loss of gene expression in methotrexate-resistant K562 human erythroleukemia cells.

Severe impairment of methotrexate membrane transport in methotrexate-resistant K562 (K500E) cells was characterized by a nearly complete loss of reduced folate carrier (RFC) transcripts and RFC protein. As determined by 5'-rapid amplification of cDNA ends (5'-RACE), approximately 93% of the RFC transcripts in wild-type cells contained the KS43 5'-untranslated region transcribed from the RFC-B promoter. KS43 transcripts decreased > 90% in K500E cells. The basal and full-length RFC-B promoters were more active (3- and 2-fold, respectively) in directing transcription of a luciferase reporter gene in K500E than in wild-type cells. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine, or with a histone deacetylase inhibitor, trichostatin A, did not increase the levels of RFC transcripts in K500E cells. No differences in RFC gene structure were detected between the lines on Southern blots; however, the RFC signals were decreased approximately 60% in K500E cells. DNA sequences were identical between the lines for the RFC coding region and the two 5'-non-coding exons and their respective promoters. Spectral karyotype analysis and fluorescence in situ hybridization in wild-type cells showed two normal chromosome 21 copies and one or two marker chromosomes, each with an RFC signal. In K500E cells, the RFC gene locus was no longer localized to a normal chromosome 21 (at 21q22.2), and a single RFC signal was associated with a small metacentric chromosome, characterized by a 21/22 translocation. Our results suggest that loss of RFC transcripts in K500E cells is unrelated to changes in the levels of critical transcription factors, or to differences in the extent of RFC promoter methylation or core histone deacetylation. Rather, this phenotype is due to the loss of one or more RFC alleles, and to a translocation of the remaining RFC allele with the formation of a 21/22 fusion chromosome.

5' Untranslated Regions↗
PubMed1996

Sequence simplicity and evolution of the 3' untranslated region of the histone H1o gene.

The H10 gene has a long 3' untranslated region (3'UTR) of 1,125 nucleotides in the rat and 1,310 in humans. Analysis of the sequences shows that they have features of simple DNA that suggest involvement of replication slippage in their evolution. These features include the length imbalance between the rat and human sequences; the abundance of single-base repeats, two-base runs and other simple motifs clustered along the sequence; and the presence of single-base repeat length polymorphisms in the rat and mouse sequences. Pairwise comparisons show numerous short insertions/deletions, often flanked by direct repeats. In addition, a proportion of short insertions/deletions results from length differences in conserved single-base repeats. Quantification of the sequence simplicity shows that simple sequences have been more actively incorporated in the human lineage than in the rodent lineage. The combination of insertions/deletions and nucleotide substitutions along the sequence gives rise to three main regions of homology: a highly variable central region flanked by more conserved regions nearest the coding region and the polyA addition site.

Animals↗
PubMed1991

Genetic polymorphism of erythrocyte histone H1 in Japanese quail.

Histone H1 from erythrocytes of Japanese quail was resolved in a sodium dodecyl sulfate (SDS)-polyacrylamide gel into five fractions differing in apparent molecular weights. A polymorphism of histone H1.1, H1.2, and H1.3 bands was detected among quail individuals. While some birds possessed either a high (phenotype .3+) or a low (phenotype .3+/.3-) level of H1.3, at least half of the quail population lacked this H1 band (phenotype .3-). Appropriate genetic crosses demonstrated that H1.3 behaved as though it was coded by a gene with two codominant alleles at an autosomal locus. Using two-dimensional polyacrylamide gel electrophoresis (acid-urea followed by SDS gels), it was found that birds .3+ contained polypeptides H1.b1 and H1.b'1; birds .3-, polypeptides H1.b2 and H1.b'2 with lower apparent molecular weights; and birds .3+/.3-, both types of polypeptides in equal proportions. The H1.b2 + H1.b'2 complement was not discernible in SDS gels, for it migrated together with H1.c' within band H1.4. It was found that a small number of birds lacking the H1.2 band in SDS gels failed to express histone H1.a. Since birds with phenotype .2- with a defective allele of the gene H1.a were simultaneously lacking the H1.3 band, it seems that the imperfect allele of the H1.a gene might be closely linked to the alleles producing H1.b2 + H1.b'2.

Animals↗
PubMed1993

Proximal promoter region of the wheat histone H3 gene confers S phase-specific gene expression in transformed rice cells.

The cis-regulatory elements that confer cell cycle-dependent expression to the wheat histone H3 gene were investigated in rice cells (Oc strain) transformed with H3/GUS chimeric genes. 5' deletion mutants of the H3 promoter region (from -1711, -908 or -185 to +57 relative to the transcription start site) were joined to the coding sequence of the bacterial beta-glucuronidase (GUS) gene then introduced stably into rice cells. S1 analyses of the RNA from transformed rice cells whose cell cycles had been synchronized by treatment with aphidicolin showed that the steady-state levels of the transcripts from chimeric genes were altered with the change in DNA synthesis and the content of rice H3 mRNA throughout the cell cycle. Even though H3 promoter activity decreased as 5' deletion proceeded, transcripts from the chimeric genes showed increases, as much as 10-fold 1 h after release from the aphidicolin block, which were rapidly lost over the next 4 h. The results suggest that the 242 bp sequence from -185 to +57, which contains the basal promoter region, confers the S phase-specific expression of the H3 gene and that the upstream sequence from position -186 is required for the full activity of this promoter.

Base Sequence↗
PubMed1978

The organization of transcription on lampbrush chromosomes.

The meiotic lampbrush chromosomes of amphibian oocytes display readily distinguishable regions of transcription (lateral loops) which extend from axial condensates of chromatin (chromomeres). The chromomeres contain most of the chromosomal ENA which, along with histone, is tightly compacted as regular arrays of DNP. Many RNA transcripts are generated on the lateral loops, and heterogeneous non-histone proteins associate with these transcripts, forming periodic condensates of 20--30 nm ribonucleoprotein (RNP) particles. These unit particles aggregate in various ways and to varying degrees and thereby confer distinctive gross morphologies to particular loops. There are about 10(4) lateral loops per haploid complement of newt chromosomes and this figure is similar to the experimentally derived number of different messenger RNA sequences found in oocytes. From cytological and biochemical studies it is now possible to consider individual lateral loops from various aspects: as morphologically distinct units; as units of inheritance; as units of functional activity; as units of transcription; as units of transcribed repetitive sequences; and as units containing one coding sequence. The difficulties in arriving at a simple explanation of the organization of transcription in lampbrush chromosomes are discussed.

Animals↗
PubMed2003

Cloning and characterization of the Drosophila U7 small nuclear RNA.

Base pairing between the 5' end of U7 small nuclear RNA (snRNA) and the histone downstream element (HDE) in replication-dependent histone pre-mRNAs is the key event in 3'-end processing that leads to generation of mature histone mRNAs. We have cloned the Drosophila U7 snRNA and demonstrated that it is required for histone pre-mRNA 3'-end processing in a Drosophila nuclear extract. The 71-nt Drosophila U7 snRNA is encoded by a single gene that is embedded in the direct orientation in an intron of the Eip63E gene. The U7 snRNA gene contains conserved promoter elements typical of other Drosophila snRNA genes, and the coding sequence is followed by a 3' box indicating that the Drosophila U7 snRNA gene is an independent transcription unit. Drosophila U7 snRNA contains a trimethyl-guanosine cap at the 5' end and a putative Sm-binding site similar to the unique Sm-binding site found in other U7 snRNAs. Drosophila U7 snRNA is approximately 10 nt longer than mammalian U7 snRNAs because of an extended 5' sequence and has only a limited potential to form a stem-loop structure near the 3' end. The extended 5' end of Drosophila U7 snRNA can base pair with the HDE in all five Drosophila histone pre-mRNAs. Blocking the 5' end of the U7 snRNA with a complementary oligonucleotide specifically blocks processing of a Drosophila histone pre-mRNA. Changes in the HDE that abolish or decrease processing efficiency result in a reduced ability to recruit U7 snRNA to the pre-mRNA.

Animals↗
PubMed2004

Epigenetic reprogramming during early development in mammals.

Epigenetic modifications serve as an extension of the information content by which the underlying genetic code may be interpreted. These modifications mark genomic regions and act as heritable and stable instructions for the specification of chromatin organisation and structure that dictate transcriptional states. In mammals, DNA methylation and the modification of histones account for the major epigenetic alterations. Two cycles of DNA methylation reprogramming have been characterised. During germ cell development, epigenetic reprogramming of DNA methylation resets parent-of-origin based genomic imprints and restores totipotency to gametes. On fertilisation, the second cycle is triggered resulting in an asymmetric difference between parental genomes. Further epigenetic asymmetry is evident in the establishment of the first two lineages at the blastocyst stage. This differentiative event sets the epigenetic characteristics of the lineages as derivatives of the inner cell mass (somatic) and trophectoderm (extra-embryonic). It is the erasure and subsequent re-tracing of the epigenetic checkpoints that pose the most serious obstacles to somatic nuclear transfer. Elaboration of the mechanisms of these interactions will be invaluable in our fundamental understanding of biological processes and in achieving substantial therapeutic advances.

Animals↗
PubMedDate not supplied

Chromatin structure: from nuclei to genes (review).

Characterization of native nuclei by new unharmful biophysical methods, coupled both with the determination of lower order structures in DNA and isolated chromatin, by a variety of sophisticated physicochemical probes and with the intranuclear DNA distribution monitored in situ by high resolution image analysis, recently, point to a unique organization of chromatin-DNA from the secondary up to the quinternary level. Based on the wide range of experimental findings, hereby reviewed in details, a three-dimensional model for DNA structure is proposed from the nuclear level down to the genes, functional units hereby associated with specific structural repeating units. This "fibrosome" model not only accounts for many of the independent observations on the physical and chemical properties of chromatin-DNA, and on the nuclear scaffold and pores, but also accounts for most recent, yet unexplained, discoveries on eukaryotic gene structure, mapping and coding, suggesting a mechanism by which gene expression and cell function may be controlled.

Animals↗