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At least 19 recordsLinked to original sources
PubMed2004

Calculating the statistical significance of physical clusters of co-regulated genes in the genome: the role of chromatin in domain-wide gene regulation.

Physical clusters of co-regulated, but apparently functionally unrelated, genes are present in many genomes. Despite the important implication that the genomic environment contributes appreciably to the regulation of gene expression, no simple statistical method has been described to identify physical clusters of co-regulated genes. Here we report the development of a model that allows the direct calculation of the significance of such clusters. We have implemented the derived statistical relation in a software program, Pyxis, and have analyzed a selection of Saccharomyces cerevisiae gene expression microarray data sets. We have identified many gene clusters where constituent genes exhibited a regulatory dependence on proteins previously implicated in chromatin structure. Specifically, we found that Tup1p-dependent gene domains were enriched close to telomeres, which suggested a new role for Tup1p in telomere silencing. In addition, we identified Sir2p-, Sir3p- and Sir4p-dependent clusters, which suggested the presence of Sir-mediated heterochromatin in previously unidentified regions of the yeast genome. We also showed the presence of Sir4p-dependent gene clusters bordering the HMRa heterothallic locus, which suggested leaky termination of the heterochromatin by the boundary elements. These results demonstrate the utility of Pyxis in identifying possible higher order genomic features that may contribute to gene regulation in extended domains.

Chromatin↗
PubMed2000

Human papillomavirus type 16 E7-regulated genes: regulation of S100P and ADP/ATP carrier protein genes identified by differential-display technology.

Human papillomavirus type 16 (HPV-16) is the dominant risk factor for the development of cervical cancer. The virus encodes three oncoproteins, of which the E7 oncoprotein is the major protein involved in cell immortalization and transformation. E7 is a multi-functional protein. It binds the retinoblastoma tumour-suppressor protein (pRb), which regulates progression through the G(1) restriction point in the cell cycle. The E7 protein interacts with transcription-regulatory proteins such as the TATA box-binding protein and with proteins of the AP1 transcription factor family. To identify additional proteins regulated by E7, differential-display PCR was used to identify differentially expressed mRNAs in cells containing an inducible E7 protein. It is reported that E7 expression leads to regulation of the genes encoding the calcium-binding protein S100P and the mitochondrial ADP/ATP carrier protein. These data identify new functions of the E7 protein and thus expand the number of routes by which HPV-16 influences cell growth control, although the function of S100P has still to be elucidated.

Calcium-Binding Proteins↗
PubMed1990

The 3'-flanking region shared by the human apolipoprotein AI and CIII gene regulates gene expression in cooperation with 5'-flanking elements.

The genes of the apolipoproteins AI and CIII are localized in opposite orientation on chromosome 11 in close vicinity, separated from each other by a non-coding intergenic region of 2.1 kb. The interdependence of their expression has been studied in cotransfection experiments in Hep G2 cells. An expression vector harboring the intergenic region with CAT as reporter gene and likewise pUC 19 derivatives with the putative cis-elements were constructed. Inhibition of gene expression by 5'-flanking elements of the apo AI and CIII gene was observed. Four proteins have been identified in nuclear extracts of Hep G2 cells that bind to several sequences of the intergenic domain but not to the 5'-flanking regions of apo AI or CIII gene. These proteins might be responsible for the silencer effect. The pathway of the regulation of apo CIII and AI expression derived from the experiments described here is supported by mutations in the intergenic region, leading to the phenotype of hypertriglyceridemia, and the stimulatory effect of cholesterol on apo AI transcription in Hep G2 cells.

Apolipoprotein A-I↗
PubMed1990

Gene regulation in macrophage activation: differential regulation of genes encoding for tumor necrosis factor, interleukin-1, JE, and KC by interferon-gamma and lipopolysaccharide.

Although macrophage activation is induced in a complex manner by signals such as interferon-gamma (IFN gamma) and bacterial lipopolysaccharide (LPS) and depends on alterations in levels of specific proteins due to differences in gene expression, the complexity of gene regulation during macrophage activation in regard to multiple signals is not fully appreciated. To probe this question, we selected four model genes encoding for tumor necrosis factor (TNF), interleukin-1 (IL-1), and the immediate early genes JE and KC. After analyses of Northern blots for specific mRNA, LPS was found to enhance levels of mRNA for IL-1, TNF, JE, and KC. IFN gamma initiated heightened mRNA levels for JE but did not alter specific mRNA for IL-1, TNF, or KC. When IFN gamma and LPS were combined, additive effects on levels of specific mRNA for JE, enhancement of mRNA for TNF, suppressed mRNA for KC, and no effect on mRNA for IL-1 were observed. When transcription of these genes was assessed by nuclear "run on" experiments, LPS increased transcription of KC and TNF but not of IL-1 or JE, implying that the increased levels of mRNA for JE and IL-1 were attributable to increased stability of mRNA. Likewise, IFN gamma did not initiate transcription of JE. When IFN gamma and LPS were given together, IFN gamma enhanced the LPS-induced transcription of TNF and KC, suggesting decreased stability of mRNA for KC. A distinct pattern of regulation for each of the four genes was thus observed. Taken together, the data suggest that gene regulation in macrophage activation represents a complex response of enhanced and suppressed transcription and mRNA stability, the precise pattern of which depends on the stimuli given to the macrophages and the gene examined.

Animals↗
PubMed1995

Evidence for functional polymorphism of the spvR gene regulating virulence gene expression in Salmonella.

The expression of Salmonella enterica spv virulence genes was studied in serovariants Dublin and Typhimurium using Western blotting (immunoblotting), spv-lacZ operon fusions and Northern blotting. The SpvA protein was detected in immunoblots from stationary phase cultures of Dublin but not from the corresponding cultures of Typhimurium. Transcriptional measurements, using a spvA-lacZ operon fusion, indicated 8-10 times higher spvA transcription in Dublin. In an isogenic Escherichia coli chromosomal background, virulence plasmids from various Dublin strains systematically had a significantly higher induction level of the spvA-lacZ operon fusion than virulence plasmids from Typhimurium strains. The cloned spvR transcriptional activator gene of Dublin strain 2229 was found to activate both spvR-lacZ and spvA-lacZ operon fusions, as well as to raise spv mRNA levels in E. coli TG1. In contrast, the corresponding cloned gene of Typhimurium strain SL2965 possessed a lower induction potential and required higher spvR gene dosage for activation. A comparison of the nucleotide sequences of spvR genes from two Dublin and four Typhimurium strains revealed conserved, serovariant-associated basepair substitutions. Our results indicate that the spv virulence gene cluster possesses different functional alleles of the regulator gene spvR. This finding has important consequences for comparative studies of regulation and virulence in different serovariants of Salmonella.

Base Sequence↗
PubMed1990

Conservation of a dual-start motif in P22 lysis gene regulation.

Gene 13 of bacteriophage P22 is functionally equivalent to lambda lysis gene S. Gene S codes for two products, the polypeptides S105 and S107, produced from translational initiation events at the third and first codon, respectively. We have shown that the two polypeptides have opposing functions in lysis: S105 is the lethal lysis effector, and S107 acts as an inhibitor of lysis (U. Bläsi, K. Nam, D. Hartz, L. Gold, and R. Young, EMBO J. 11:3501-3510, 1989). Gene 13 has a 108-codon reading frame and its product begins with a similar motif: Met-1-Lys-2-Lys-3-Met-4. Here, we present in vivo and in vitro evidence for the expression of a 13(108) and a 13(105) product and show that the lambda lysis control mechanisms is evolutionarily conserved in phage P22. In this case 13(108), like S107 in lambda, functions as the inhibitor of the lysis effector 13(105). Although the DNA sequences upstream of the S and 13 gene starts showed less homology, the same structural characteristics, i.e., stem-loop structures immediately upstream and about 10 codons downstream of the start region, were present in both reading frames. Using in vitro mutagenesis and toeprinting, we show that the upstream stem-loop structures of genes 13 and S, containing the Shine-Dalgarno sequence for initiations at Met-1, are interchangeable. Moreover, our data indicate that the stability of the secondary structures present in the translational initiation regions of genes S and 13 is set to create a particular ratio of initiation events at Met-1 and Met-3 or Met-4. The ratio of effector to inhibitor was much higher in P22 than in lambda. We propose that this reflects less transcriptional readthrough at the late terminator t(R) and suggests that the dual-start motif in genes 13 and S may be important for establishment of maintenance of the lysogenic state.

Base Sequence↗
PubMed2003

Candida albicans response regulator gene SSK1 regulates a subset of genes whose functions are associated with cell wall biosynthesis and adaptation to oxidative stress.

Ssk1p of Candida albicans is a putative response regulator protein of the Hog1 two-component signal transduction system. In Saccharomyces cerevisiae, the phosphorylation state of Ssk1p determines whether genes that promote the adaptation of cells to osmotic stress are activated. We have previously shown that C. albicans SSK1 does not complement the ssk1 mutant of S. cerevisiae and that the ssk1 mutant of C. albicans is not sensitive to sorbitol. In this study, we show that the C. albicans ssk1 mutant is sensitive to several oxidants, including hydrogen peroxide, t-butyl hydroperoxide, menadione, and potassium superoxide when each is incorporated in yeast extract-peptone-dextrose (YPD) agar medium. We used DNA microarrays to identify genes whose regulation is affected by the ssk1 mutation. RNA from mutant cells (strain CSSK21) grown in YPD medium for 3 h at 30 degrees C was reverse transcribed and then compared with similarly prepared RNA from wild-type cells (CAF2). We observed seven genes from mutant cells that were consistently up regulated (three-fold or greater compared to CAF2). In S. cerevisiae, three (AHP1, HSP12, and PYC2) of the seven genes that were up regulated provide cells with an adaptation function in response to oxidative stress; another gene (GPH1) is regulated under stress conditions by Hog1p. Three other genes that are up regulated encode a cell surface protein (FLO1), a mannosyl transferase (MNN4-4), and a putative two-component histidine kinase (CHK1) that regulates cell wall biosynthesis in C. albicans. Of the down-regulated genes, ALS1 is a known cell adhesin in C. albicans. Verification of the microarray data was obtained by reverse transcription-PCR for HSP12, AHP1, CHK1, PYC2, GPH1, ALS1, MNN4-4, and FLO1. To further determine the function of Ssk1p in the Hog1p signal transduction pathway in C. albicans, we used Western blot analysis to measure phosphorylation of Hog1p in the ssk1 mutant of C. albicans when grown under either osmotic or oxidative stress. We observed that Hog1p was phosphorylated in the ssk1 mutant of C. albicans when grown in a hyperosmotic medium but was not phosphorylated in the ssk1 mutant when the latter was grown in the presence of hydrogen peroxide. These data indicate that C. albicans utilizes the Ssk1p response regulator protein to adapt cells to oxidative stress, while its role in the adaptation to osmotic stress is less certain. Further, SSK1 appears to have a regulatory function in some aspects of cell wall biosynthesis. Thus, the functions of C. albicans SSK1 differ from those of S. cerevisiae SSK1.

Adaptation, Physiological↗
PubMed2001

Targeted gene regulation and gene ablation.

Investigations of the mechanisms involved in appropriate, developmentally regulated tissue-specific gene transcription have laid the foundations for transgenic and gene-therapy technologies directing specific induction or ablation of genes of interest in a tissue-restricted manner. This technology has further evolved to allow for temporal control of gene expression and ablation. Genes can now be switched on and off or be ablated by administering exogenous compounds. These technologies are based on the development of ligand-inducible transcription factors or recombinases that regulate gene expression or ablation by the administration of specific ligands and should lead to animal models that are better suited for investigating the molecular basis of human disease. This review describes the evolution, components and applications of systems that are currently being employed in transgenic and mutant-mouse technology for the conditional regulation of gene expression and ablation.

Animals↗
PubMed2024

Adaptation for Staphylococcus aureus to hosts via insertion mutation in the accessory gene regulator agrC gene: decreased virulence and enhanced persistence capacity.

UNLABELLED: Staphylococcus aureus is an important human pathogen due to its vast array of virulence factors regulated by multiple regulatory mechanisms, including the accessory gene regulator. In this study, two S. aureus strains were simultaneously isolated from the blood of a febrile patient, belonging to the same clone, designated as 23H with a complete hemolytic phenotype, and 23B, exhibiting an incomplete hemolytic phenotype. The genomic comparison between strains 23B and 23H revealed that 23B had a single adenine base insertion at position 923 in the agrC gene, leading to a functional loss of the encoded AgrC. Experimental findings showed that strain 23B had decreased hemolytic activity, lower cytotoxicity against human alveolar epithelial A549 cells and in the Galleria mellonella model, and a reduced ability to survive intracellularly after infecting macrophages, in comparison to 23H. Conversely, 23B exhibited enhanced biofilm formation, greater adherence to A549 cells, and increased persistence in the face of vancomycin and daptomycin treatment. Transcriptomic analysis revealed that 23B upregulated surface protein-encoding genes while simultaneously reducing the expression levels of virulence factors, highlighting the intricate regulatory adjustments facilitating its persistence and reducing pathogenic potential. ATP assay results indicated that 23B maintained elevated ATP levels during the exponential phase yet exhibited reduced levels in the stationary phase when compared with 23H. Our findings suggested that the mutation in the agrC gene of S. aureus results in diminished virulence but markedly enhances persistence. This mutated strain warrants clinical attention because it may lead to treatment failures and persist in patients. IMPORTANCE: In clinical antimicrobial therapy, bacterial strains often develop resistance to antimicrobial agents. Additionally, mutations in their gene regulatory networks can increase their persistence, especially in immunocompromised patients. This study identified an insertion mutation in the accessory gene regulator, agrC gene, carried by a Staphylococcus aureus strain isolated from the blood of a febrile patient, leading to the functional loss of AgrC. Further research revealed that despite the reduced virulence of the mutated strain, it significantly bolstered the capacity to adapt and endure within the host during prolonged infections. This was evidenced by increased adhesion and biofilm formation capabilities, development of antimicrobial tolerance, and decreased ATP levels linked to persistence. Therefore, monitoring these mutations in S. aureus is crucial clinically, as they can complicate treatment strategies.

Staphylococcus aureus↗
PubMed1997

A Polycomb-group gene regulates homeotic gene expression in Arabidopsis.

Cell fate is determined when the commitment of cells to a particular fate is autonomously maintained, irrespective of their environment. In Drosophila, fate determination is maintained through the action of the Polycomb-group and trithorax-group genes, which are required so that states of homeotic gene activity are inherited through cell division. It is shown here that the CURLY LEAF gene of Arabidopsis is necessary for stable repression of a floral homeotic gene and encodes a protein with homology to the product of the Polycomb-group gene Enhancer of zeste. We suggest that Polycomb-group genes have a similar role in fate determination in plants and animals.

AGAMOUS Protein, Arabidopsis↗
PubMed1986

Pharmacological characterization of cyclic AMP receptors mediating gene regulation in Dictyostelium discoideum.

Extracellular molecules regulate gene expression in eucaryotes. Exogenous cyclic AMP (cAMP) affects the expression of a large number of developmentally regulated genes in Dictyostelium discoideum. Here, we determine the specificity of the receptor(s) which mediates gene expression by using analogs of cAMP. The order of potency with which these analogs affect the expression of specific genes is consistent with the specificity of their binding to a cell surface receptor and is distinct from their affinity for intracellular cAMP-dependent protein kinase. Dose-response curves with cAMP and adenosine 3',5'-monophosphorothioate, a nonhydrolyzable analog, revealed that the requirement for high concentrations of exogenous cAMP for regulating gene expression is due to the rapid degradation of cAMP by phosphodiesterase. The addition of low concentrations of cAMP (100 nM) or analogs in pulses also regulates gene expression. Both the genes that are positively regulated by exogenous cAMP and the discoidin gene, which is negatively regulated, respond to cAMP analogs to the same degree. Genes expressed in prespore or prestalk cells are also similarly regulated. These data suggest that the effects are mediated through the same receptor. The specificity of this receptor is indistinguishable from that of the well-characterized cell surface cAMP receptor.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Retinoids and receptor interacting protein 140 (RIP140) in gene regulation.

Retinoids exert pleiotropic effects in various biological processes by binding to their nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), to regulate gene transcription. Apo-RARs and RXRs repress target gene expression by recruiting corepressors to the target DNA, triggering chromatin condensation by the action of histone deacetylases present in the corepressor complexes. In contrast, holo-RARs and RXRs recruit coactivators, some known to encode histone acetyl transferases, which trigger histone hyperacetylation, chromatin decondensation, and ultimately gene activation. Receptor interacting protein 140 (RIP140) represents a novel RAR/RXR coregulator that suppresses vitamin A-regulated gene expression in a retinoid- dependent manner. This review addresses the action of different retinoid ligands on gene expression, the molecular mechanisms underlying RAR/RXR-mediated gene regulation, and the unique properties of RIP140 as a novel retinoid hormone-dependent negative coregulator for RAR- and RXR-mediated gene regulation.

Adaptor Proteins, Signal Transducing↗
PubMed1986

[Identification of the nucleotide sequences specific for the 5'-flanking regions of the genes regulated by glucocorticoids by a computer analysis method].

Nucleotide sequences of 5'-flanking regions of 11 glucocorticoid-regulated genes and 14 genes non-regulated by these hormones were studied using context computer analysis. Consensus TGTTCT, previously found in DNA fragments protected by glucocorticoid-receptor complexes from DNAase I digestion, was shown to be nonspecific for glucocorticoid-regulated genes. However, the analysis of sequences flanking the TGTTCT consensus has revealed that only glucocorticoid-regulated genes contain four regularly distributed cytosine residues, one of them belonging to TGTTCT consensus. Three of cytosine residues are separated by 8-10 bp, which provides their close neighbourhood at one side of DNA double helix; the fourth extreme cytosine residue is located 6 bp from the nearest one and therefore, the complementary guanine residue is adjacent to the consensus in DNA helix. It is suggested that the consensus itself and two flanking cytosine and one guanine residues form a specific site for the interaction with glucocorticoid-receptor complex.

Animals↗
PubMed2004

Analysis of ataxia-telangiectasia mutated (ATM)- and Nijmegen breakage syndrome (NBS)-regulated gene expression patterns.

PURPOSE: Ataxia-telangiectasia (A-T) is a progressive, degenerative, complex autosomal recessive disease characterized by cerebellar degeneration, immunodeficiency, premature aging, radiosensitivity, and a predisposition to cancer. Mutations in the ataxia-telangiectasia mutated (atm) gene, which phosphorylates downstream effector proteins, are linked to A-T. One of the proteins phosphorylated by the ATM protein is Nijmegen Breakage Syndrome protein (NBS, p95/nibrin), which was recently shown to be encoded by a gene mutated in the Nijmegen breakage syndrome (nbs), an autosomal recessive disease with a phenotype virtually similar to that of A-T. The similarities in the clinical and cellular features of NBS and A-T have led us to hypothesize that the two corresponding gene products may function in similar ways in the cellular signaling pathway. Thus, we sought to identify genes whose expression is mediated by the atm and nbs gene products. MATERIAL AND METHODS: To identify genes, we performed an analysis of oligonucleotide microarrays using the appropriate cell lines, isogenic A-T (ATM-) and control cells (ATM+), and isogenic NBS (NBS-) and control cells (NBS+). RESULTS: We examined genes regulated by ATM and NBS, respectively. To determine the effect of ATM and NBS on gene expression in detail, we classified these genes into different functional categories, including those involved in apoptosis, cell cycle/DNA replication, growth/differentiation, signal transduction, cell-cell adhesion, and metabolism. In addition, we compared the genes regulated by the ATM and NBS to determine the relationship of their signaling pathways and to better understand their functional relationship. CONCLUSIONS: We found that, while ATM and NBS regulate several genes in common, both of these proteins also have distinct patterns of gene regulation, findings consistent with the functional overlap and distinctiveness of these two conditions. Due to the role of ATM and NBS in tumor suppression and the response to chemotherapy and radiotherapy, these findings may assist in the development of a more rational approach to cancer treatment, as well as a better understanding of tumorigenesis.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1997

PhoP/Q regulated genes in Salmonella typhi identification of melittin sensitive mutants.

Many of the genes (pags (phoP activated genes) and prgs (phoP repressed genes)) regulated by the PhoP and PhoQ proteins (PhoP/Q) are necessary for survival of Salmonella typhimurium in murine macrophages and pathogenesis in mice. Although a great deal is known about the S. typhimurium phoP/Q regulon, little has been done with the human specific pathogen S. typhi, prompting us to investigate S. typhi phoP/Q regulated genes. Isogenic phoP12 (null) and phoP24 (constitutive) strains were constructed in S. typhi Ty2 and S. typhimurium C5 strains. Comparison of whole cell proteins from these strains by SDS-PAGE showed differences in both the number and molecular mass of PhoP/Q regulated proteins. This suggested that S. typhi and S. typhimurium may have different PhoP/Q regulated proteins and/or that their regulation may be different. A genetic procedure was developed to isolate mutations in PhoP/Q regulated genes. This involved random MudJ transposon mutagenesis of a phoP12 mutant, creating lacZ-gene fusions, and screening for Lac+ or Lac- colonies. A mobilizable plasmid carrying the phoP24 mutant gene was conjugated into these insertion mutants. Those that changed from Lac- to Lac+ were inferred to be pag::MudJ insertions and those that changed from Lac+ to Lac- were inferred to be prg::MudJ insertions. Five mutants with PhoP/Q regulated MudJ fusions were found by this scheme. The mutations were termed pqa (PhoPQ activated) and pqr (PhoPQ repressed) to distinguish them from other PhoP/Q regulated genes. The pqa/pqr::MudJ mutations were transduced into S. typhi phoP+ and phoP24 strains by Vi-l phage transduction. Characterization of the mutants (Southern blot analysis, beta-galactosidase activity on indicator plates and in liquid cultures) strongly suggested that their MudJ insertion mutations were in five different genes. Further characterization involved determining cationic peptide sensitivity and mouse virulence. Two mutants were found to be sensitive to the antimicrobial peptide melittin.

Animals↗
PubMed2002

Rationalization of gene regulation by a eukaryotic transcription factor: calculation of regulatory region occupancy from predicted binding affinities.

DNA-binding proteins regulate gene expression by binding preferentially to a set of related sequences. In order to quantify the correlation between gene regulation and the presence of sequence motifs, the affinity of a transcription factor for each variant of the binding site must be known or predicted. In addition, the contribution of multiple binding sites to the regulation of a single gene must be modeled. To predict the affinity of the yeast Leu3 transcription factor for genomic-binding sites, we measured the in vitro equilibrium dissociation constants of 43 binding-site variants and established that the free energy of binding can be approximated as a sum of free energy contributions from each base-pair. This allows the prediction of an equilibrium dissociation constant for all potential binding sites in the genome and, therefore, their fractional occupancy at some assumed concentration of free Leu3. From the occupancy of individual sites, the probability that at least one site is occupied within a defined segment upstream of a gene was calculated for all genes in yeast. We find that this probability is substantially better correlated with regulation by Leu3 than is the number of binding sites. This is true whether the number of binding sites is based on a consensus site definition of the binding site or by enumeration of all variants that have a predicted K(d) value below some threshold. The occupancy calculation was best able to rationalize the Leu3-regulated gene set over a Leu3 concentration range that spans the K(d) values for the best sites.

Base Sequence↗