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Results for “Locus Control Region”

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PubMed1989

A dominant control region from the human beta-globin locus conferring integration site-independent gene expression.

The regulatory elements that determine the expression pattern of a number of eukaryotic genes expressed specifically in certain tissues have been defined and studied in detail. In general, however, the expression conferred by these elements on genes reintroduced into the genomes of cell lines and transgenic animals has turned out to be at a low level relative to that of endogenous genes, and influenced by the chromosomal site of insertion of the exogenous construct. We have previously shown that if regions flanking the human beta-globin locus are introduced into the mouse genome along with the human beta-globin gene, a level of expression comparable to that of endogenous genes can be achieved that is also independent of integration site. We have now defined a dominant control region with these properties consisting of 6.5 kilobases of DNA encompassing erythroid cell-specific DNase I hypersensitive sites. The identification of such dominant control regions could have important applications in somatic gene therapy.

Animals↗

PubMed1989

Analysis of the promoter region of the melanin locus from Streptomyces antibioticus.

Several approaches were used to study the transcriptional control region of the melanin-production locus (melC) of Streptomyces antibioticus. Filter-binding in combination with exonuclease III protection localized the 3' boundary of a Streptomyces RNA polymerase-binding site predominantly about 39 nucleotides (nt) upstream from the start codon of melC1, the first open reading frame in the melC locus. Deletion of nt 112-197 upstream from the melC1 start codon reduced melC expression to less than 10%, and deletion of nt 28-107 or 28-120 upstream from melC1 totally inactivated melC. High-resolution nuclease S1 mapping identified the in vitro transcriptional start point (tsp) at 33-34 nt upstream from the start codon of melC1. No sequence resembling the E. coli consensus promoter sequence was found in this region, and site-directed mutagenesis of such a sequence located 101-132 nt upstream from melC1 did not influence melC expression. These studies suggest that transcription of melC is principally from a single tsp and is positively regulated by a mechanism that involves sequences 87-163 nt upstream from the tsp.

Base Sequence↗

PubMed1979

Organization of the rosy locus in Drosophila melanogaster: further evidence in support of a cis-acting control element adjacent to the xanthine dehydrogenase structural element.

The present report summarizes our recent progress in the genetic dissection of an elementary genetic unit in a higher organism, the rosy locus (ry:3--52.0) in Drosophila melanogaster. Pursuing the hypothesis that the rosy locus includes a noncoding control region, as well as a structural element coding for the xanthine dehydrogenase (XDH) peptide, experiments are described that characterize and map a rosy locus variant associated with much lower than normal levels of XDH activity. Experiments are described that fail to relate this phenotype to alteration in the structure of the XDH peptide, but clearly associate this character with variation in number of molecules of XDH per fly. Large-scale fine-structure recombination experiments locate the genetic basis for this variation in the number of molecules of XDH per fly to a site immediately to the left of the XDH structural element within a region previously designated as the XDH control element. Moreover, experiments clearly separate this "underproducer" variant site from a previously described "overproducer" site within the control region. Examination of enzyme activity in electrophoretic gels of appropriate heterozygous genotypes demonstrates the cis-acting nature of this variation in the number of molecules of XDH. A revision of the map of the rosy locus, structural and control elements is presented in the light of the additional mapping data now available.

Crosses, Genetic↗

PubMed1987

A gene locus controlling a serum protein migrating electrophoretically in the beta region of mice and detected by using a strain derived from the Japanese wild mouse (Mus musculus molossinus).

Antigenic specificities of serum proteins from the MOL-ANJ strain of mice (a strain derived from Japanese wild mice, Mus musculus molossinus) were studied by gel precipitation with alloantisera produced by reciprocal alloimmunization between MOL-ANJ and BALB/c mice. An alloantigen which migrates immunoelectrophoretically in the beta region of serum proteins has been identified. Evidence indicates that this antigenic specificity is controlled by a co-dominant autosomal gene locus designated by the symbol Sas-2. The evidence also suggests that Sas-2 is genetically different from the previously described Sas-1 which controls a serum protein in the mouse. Sas-2 was located by linkage analysis between Idh-1 locus and Akp-1 locus on chromosome 1.

Animals↗

PubMed1986

Separation of the functions controlled by adenovirus 2 lp+ locus.

The adenovirus lp+ locus is located within early region E1b (map position 4.5-11.2) and codes for a 19-kDa tumor antigen (175R). Genetic analysis of the viral mutants that map within this region indicates that the lp+ locus controls multiple functions in cell transformation and in productive viral infection. Viral mutants mapping within the lp+ locus produce wt-like cytopathic effect (cyt+) or a cytocidal (cyt) effect. Earlier results have shown that many of the viral mutants that produce cyt phenotype in infected cells are transformation defective. In the present studies we show that one of the cyt mutants, cyt 106 which has a single amino acid substitution at position 20 transforms the established rat embryo cell line, CREF, at somewhat reduced frequency. Nonetheless, the cyt106-transformed cells appear to be fully transformed when compared with Ad2 wild type transformed cells. Unlike most other cyt mutants, cyt 106 is dominant over Ad2 wild type in mixed infections as judged by the plaque morphology in infective center assays and by the cytopathic effect. The dominant nature of the mutation may contribute to the observed transformation characteristics. Earlier we have shown that a cytocidal mutant, dl250 is partially defective in viral DNA synthesis in human KB cells. Now we show that two other cyt mutants cyt 5 (with a chain termination mutation near the C terminus) and cyt 6 (with a single amino acid substitution at position 44) are also partially defective in viral DNA synthesis in human KB cells. In contrast to these mutants, mutant cyt 106 induces normal replication of viral DNA. The DNA replication defect in mutants cyt 5 and 6 can be complemented in trans in 293 cells that constitutively express the 175R T antigen. Our results also indicate that a domain of this protein around the 44th amino acid is important for efficient viral DNA synthesis in KB cells.

Adenoviridae↗

PubMed1988

Mini-P1 plasmid replication: the autoregulation-sequestration paradox.

It has been proposed that the initiator protein RepA is rate limiting for mini-P1 plasmid replication, and that the role of the plasmid copy number control locus is to sequester the initiator and thus reduce replication. This proposal appears inconsistent with the observation that RepA is autoregulated, since the protein lost by sequestration should be replenished. A resolution of this autoregulation-sequestration paradox is possible if the sequestered RepA, unavailable for replication, is still available for promoter repression. We demonstrate that RepA binds to the control locus and to the promoter region simultaneously, causing the intervening DNA to loop. DNA looping could provide the requisite mechanism by which RepA bound to the control locus might exert repression.

DNA Helicases↗

PubMed1990

Tandem AP-1-binding sites within the human beta-globin dominant control region function as an inducible enhancer in erythroid cells.

A powerful enhancer has been mapped to an 18-bp DNA segment located 11 kb 5' to the human epsilon-globin gene within the dominant control or locus-activating region. This enhancer is inducible in K562 human erythroleukemia cells, increasing linked gamma-globin promoter/luciferase gene expression to 170-fold over an enhancerless construct. The enhancer consists of tandem AP-1-binding sites, phased 10 bp apart, which are both required for full activity. DNA-protein binding assays with nuclear extracts from induced cells demonstrate a high molecular weight complex on the enhancer. The formation of this complex also requires both AP-1 sites and correlates with maximal enhancer activity. Induction of the enhancer may have a role in the increase in globin gene transcription that characterizes erythroid maturation. Enhancer activity appears to be mediated by the binding of a complex of proteins from the jun and fos families to tandem AP-1 consensus sequences.

Base Sequence↗

PubMed1975

Induction of cytotoxic T lymphocytes against I-region-coded determinants: in vitro evidence for a third histocompatibility locus in the mouse.

Determinants controlled by the I region of the murine H-2 complex provoked the generation of cytotoxic T lymphocytes (CTL) in both a secondary and primary mixed lymphocyte culture. The stimulating determinants appeared to be controlled by loci within the I-A subregion. The target antigens of the CTL generated were present on both lipopolysaccharide- and concanavalin-induced blast lymphocytes, but were barely detectable on phytohemagglutinin-induced blast cells. The stimulating capacity for CTL induction of a complete H-2 complex incompatibility by far exceeded the sum of H-2D/K-region and I-region incompatibility, respectively.

Animals↗

PubMed1976

The major histocompatibility complex of the guinea-pig. II. Relationship between mixed leucocyte reactivity and serologically-defined phenotypes of the GPLA B locus and I region.

The relationship between the mixed leucocyte reaction (MLR) and the serologically-defined antigens controlled by genes in the guinea-pig B locus (equivalent to the murine D or K region) and I region was investigated in various inbred and partially inbred strains and in guinea-pig families homozygous for their GPLA alleles. No MLR reactions could be detected among guinea-pig families of a closed colony which had been bred to homozygosity for their GPLA antigens. By contrast, animals which differed in their I region showed strong MLR reactivity. Animals with identical I regions as judged by four serologically-defined specificities only, but differ with respect to B locus determinants, yield appreciably lower MLR responses. It appears that in the guinea-pig, as in other mammalian species, the antigenic systems responsible for MLR reactivity are controlled primarily by genes identical with or closely linked to the I region of the major histocompatibility complex.

Animals↗

PubMed1977

The private specificity H-2.4 and the public specificity H-2.28 of the D region are expressed on two independent polypeptide chains.

The antigenic specificities H-2.4 (private) and H-2.28 (public) in the H-2a haplotype are controlled by the D region of H-2 as defined by the available recombinants. In previous studies we have demonstrated by the antibody-induced redistribution method that the antisera against these specificities contain antibodies against at least two different polypeptide chains. We here report the results of the indirect immunoprecipitation of radiolabeled antigens after solubilization with Nonidet-P40. The antisera against the two specificities precipitated from such extracts two different and independent polypeptide chains, indicating that the products of the D region, as presently defined, comprise at least two different molecules. The molecular weight of both chains is approximately 45 000, which is similar to other molecules bearing private H-2 antigenic specificities. Consequently, the chromosomal segment presently defined by recombination studies as the D region, must contain another locus, controlling the second polypeptide chain which is detectable by anti-H-2.28 antisera, besides the H-2D locus which controls the polypeptide chain bearing the private specificity H-2.4 as well as most of the public specificities.

Animals↗

PubMed1982

Regulation of expression of the dadA gene encoding D-amino acid dehydrogenase in Escherichia coli: analysis of dadA-lac fusions and direction of dadA transcription.

The catabolism of most d-amino acids is carried out by d-amino dehydrogenase, coded by the dadA gene. Employing Mud(Aprlac) phage (Casadaban and Cohen 1979) the lac structural gene were fused to the control region of the dadA locus. Expression the of the lacZ gene in the dad-lac fusions was shown to be inducible by alanine and catabolite-repressible, thus responding to regulatory signals known to affect expression of the dadA gene. The method of MacNeil et al. (1980) was adopted to transfer the chromosomal dadA-lac fusion into lambda phage. By use of isolated lambda ddadA-lac1 phage, the promoter for the dadA gene was located, which enabled determination of the direction of dadA transcription as being counter-clockwise.

Bacteriophage lambda↗

PubMed1990

Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster.

Synthesis of normal human hemoglobin A, alpha 2 beta 2, is based upon balanced expression of genes in the alpha-globin gene cluster on chromosome 16 and the beta-globin gene cluster on chromosome 11. Full levels of erythroid-specific activation of the beta-globin cluster depend on sequences located at a considerable distance 5' to the beta-globin gene, referred to as the locus-activating or dominant control region. The existence of an analogous element(s) upstream of the alpha-globin cluster has been suggested from observations on naturally occurring deletions and experimental studies. We have identified an individual with alpha-thalassemia in whom structurally normal alpha-globin genes have been inactivated in cis by a discrete de novo 35-kilobase deletion located approximately 30 kilobases 5' from the alpha-globin gene cluster. We conclude that this deletion inactivates expression of the alpha-globin genes by removing one or more of the previously identified upstream regulatory sequences that are critical to expression of the alpha-globin genes.

Adult↗

PubMed1981

A small genetic region that controls dihydroorotate dehydrogenase in Drosophila melanogaster.

A locus is described that controls levels of mitochondrial dihydroorotate dehydrogenase (EC 1.3.3.1) in Drosophila melanogaster. The effects of alleles of the locus, Dhod, are manifest in preparations from whole organisms as well as in partially purified mitochondrial preparations; however, other mitochondrial functions do not appear to be appreciably affected by Dhod genotypes. The locus maps near p in the proximal portion of the right arm of chromosome 3. Flies trisomic for a chromosome segment including that region display elevated enzyme levels, implying that an enzyme structural gene is in that vicinity. Furthermore, Dhod alleles are semidominant in heterozygotes, suggesting that the dosage-sensitive element detected in the trisomics is actually the Dhod locus. These findings are discussed relative to the role of dihydroorotate dehydrogenase in the de novo pyrimidine biosynthetic pathway and relative to other pathway mutants that have been described in Drosophila.

Animals↗

PubMed1985

Monoclonal antibody characterization of a unique immune response control locus between H-2S and D.

The primary in vitro antibody response to the type 2 antigen, trinitrophenyl (TNP)-Ficoll, is controlled by two complementing loci in the H-2 region of the mouse major histocompatibility complex (MHC). High responder alleles at both loci are necessary for a high responder phenotype. Previous studies mapped one locus of control to the I-A subregion. In this report we demonstrate by recombinant analysis that the second locus of control is located between the H-2S and D regions. A comparison of responses in the B10.BAR6, B10.BAR10, and B10.BAR11 strains defined a locus controlling the response to TNP-Ficoll in a single haplotype, bounded on the left by the crossover event in the B10.BAR10 and on the right by the crossover event in the B10.BAR6 strain. A monoclonal antibody directed against this right-hand region of control has been produced (48.21.7) that blocks the response to TNP-Ficoll at the level of the antigen-presenting cell. The monoclonal antibody 48-21.7 is specific for the high responder b allele at the right-hand locus and did not inhibit responses to other protein antigens tested. The immune response to TNP-Ficoll was not inhibited by monoclonal antibodies that react with H-2Db or Qa-2 specificities, suggesting that the TNP-Ficoll response is controlled by a unique locus located between H-2S and D. Finally, 48-21.7 recognizes and precipitates a unique product of approximately 40,000 mol wt that is distinct from the H-2D region product recognized by the monoclonal antibody B22/249.

Animals↗

PubMed1977

Serum esterase genetics in rabbits. IV. The prealbumin and beta-globulin systems.

Discontinuous starch gel electrophoresis revealed a fourth allele of rabbit pre-albumin serum esterase at locus Est-2. This allele is designated Est-2f and appears to be silent. In addition to the prealbumin serum esterases, another serum esterase system was studied in rabbits. This system is localized in the beta-globulin region. Genetic analysis indicated that one locus with two codominant alleles controls the variation in this region. Linkage of this system with Est-1 and Est-2 of the prealbumin serum esterases was demonstrated. Comparison of the arrangement of these esterase loci on linkage group VI with the esterase loci on chromosome 8 of the mouse gives additional support for the theory of evolutionary conservation of chromosomal segments coding for mammalian esterases.

Alleles↗

PubMed1987

Effects of preoptic microinjections of alpha-MSH on fever and normal temperature control in rabbits.

alpha-MSH within the septal region of the brain has been implicated in fever control; this peptide and ACTH (1-24), which contains the alpha-MSH amino acid sequence, reduce fever when given intracerebroventricularly (ICV) or peripherally. These peptides also cause hypothermia when given in doses larger than those required to reduce fever. Both peptides occur naturally within the preoptic PO region of the brain, the CNS locus of primary temperature control. alpha-MSH (350 ng) injected bilaterally into the PO region via chronic cannulas reduced fever caused in six rabbits by IV injection of IL-1 (interleukin 1, endogenous or leukocyte pyrogen) but had no effect in afebrile animals. A larger dose (1.5 micrograms) not only reduced fever but caused hypothermia in 12 rabbits. In separate experiments PO injections of ACTH (1-24) (1 microgram) reduced normal temperature. In the same six rabbits alpha-MSH (1 microgram) caused slightly smaller hypothermia. alpha-MSH (1.5 micrograms) also had no effect in 8 afebrile rabbits when injected into the septum. The primary conclusion is that alpha-MSH receptors within the PO region can contribute to both the antipyretic and hypothermic actions that are observed after ICV and peripheral administration of the peptide.

Animals↗

PubMedDate not supplied

Health Locus of Control in Chukotka children.

Two groups of children in the cities of Anadyr and Pevek in the Chukotka Region of the Soviet Far East were administered a Russian translation of the Children's Health Locus of Control Scale in July, 1991. Results were analyzed to assess the similarities between response patterns among the Russian children and those found in American children. The analyses revealed a consistency in the data suggesting both face and theoretical validity of the Scale. It appears that the underlying mediating variable related to the children's perceived control over their health is operating in this Region of Russia in much the same way that it does in the United States.

Adolescent↗

PubMed1990

Conservation of the primary structure, organization, and function of the human and mouse beta-globin locus-activating regions.

DNA sequences located in a region 6-18 kilobases (kb) upstream from the human epsilon-globin gene are known as the locus-activating region (LAR) or dominant control region. This region is thought to play a key role in chromatin organization of the beta-like globin gene cluster during erythroid development. The beta-globin LAR activates linked globin genes in transiently or stably transfected erythroleukemia cells and in erythroid cells of transgenic mice. Since the human beta-globin LAR is functional in mice, we reasoned that critical LAR sequence elements might be conserved between mice and humans. We therefore cloned murine genomic sequences homologous to one portion of the human LAR (site II, positions -11,054 to -10,322 with respect to the human epsilon gene). We found that this murine DNA fragment (mouse LAR site II) and sequences homologous to human LAR sites I and III are located upstream from the mouse beta-like globin gene cluster and determined that their locations relative to the cluster are similar to that of their human counterparts. The homologous site II sequences are 70% identical between mice and humans over a stretch of approximately 800 base pairs. Multiple core sequences with greater than 80% identity were present within this region. Transient and stable transfection assays of K562 erythroleukemia cells demonstrated that both human and mouse LAR elements contain enhancer activity and confer hemin inducibility on a linked human gamma-globin promoter. These results suggest that primary structural elements--and the spatial organization of these elements--are important for function of the beta-globin LAR.

Animals↗