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Results for “Enhancer mapping”

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PubMed2005

Genome-wide associations of gene expression variation in humans.

The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs) with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis-) to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I) HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

Chromosome Mapping↗

PubMed2005

A map of the human genome in linkage disequilibrium units.

Two genetic maps with additive distances contribute information about recombination patterns, recombinogenic sequences, and discovery of genes affecting a particular phenotype. Recombination is measured in morgans (w) over a single generation in a linkage map but may cover thousands of generations in a linkage disequilibrium (LD) map measured in LD units (LDU). We used a subset of single nucleotide polymorphisms from the HapMap Project to create a genome-wide map in LDU. Recombination accounts for 96.8% of the LDU variance in chromosome arms and 92.4% in their deciles. However, deeper analysis shows that LDU/w, an estimate of the effective bottleneck time (t), is significantly variable among chromosome arms because (i) the linkage map is approximated from the Haldane function, then adjusted toward the Kosambi function that is more accurate but still exaggerates w for all chromosomes, especially shorter ones; (ii) the non-pseudoautosomal region of the X chromosome is subject to hemizygous selection; and (iii) at resolution less than approximately 40,000 markers per w, there are indeterminacies (holes) in the LD map reflecting intervals of very high recombination. Selection and stochastic variation in small regions must have effects, which remain to be investigated by comparisons among populations. These considerations suggest an optimal strategy to eliminate holes quickly, greatly enhance the resolution of sex-specific linkage maps, and maximize the gain in association mapping by using LD maps.

Chromosome Mapping↗

PubMed1995

Functional mapping-guided resection of low-grade gliomas.

In summary, evidence exists with quantitative volumetric resection of low-grade gliomas in adults and children that a greater extent of tumor resection affects the time to tumor recurrence and the recurrent tumor phenotype. Radical resections of infiltrating low-grade glial tumors may be enhanced with the aid of intra-operative mapping methods to identify sensory, motor, and language cortex. Subcortical, descending functional pathways within white matter may also be localized using these techniques. For patients with intractable epilepsy associated with a low-grade glioma, optimal control of seizure activity, without anti-epileptic medication, is often made possible with the use of electrocorticography before and following the tumor resection, as opposed to lesion resection alone.

Brain Mapping↗

PubMed1992

Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers.

The Moloney murine leukemia virus causes thymic leukemias when injected into newborn mice. A major genetic determinant of the thymic disease specificity of the Moloney virus genetically maps to two protein binding sites in the Moloney virus enhancer, the leukemia virus factor b site and the adjacent core site. Point mutations introduced into either of these sites significantly shifts the disease specificity of the Moloney virus from thymic leukemia to erythroleukemia (N. A. Speck, B. Renjifo, E. Golemis, T. Frederickson, J. Hartley, and N. Hopkins, Genes Dev. 4:233-242, 1990). We have purified several polypeptides that bind to the core site in the Moloney virus enhancer. These proteins were purified from calf thymus nuclear extracts by selective pH denaturation, followed by chromatography on heparin-Sepharose, nonspecific double-stranded DNA-cellulose, and core oligonucleotide-coupled affinity columns. We have achieved greater than 13,000-fold purification of the core-binding factors (CBFs), with an overall yield of approximately 19%. Analysis of purified protein fractions by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis reveals more than 10 polypeptides. Each of the polypeptides was recovered from an SDS-polyacrylamide gel, and those in the molecular size range of 19 to 35 kDa were demonstrated to have core-binding activity. The purified CBFs were shown by DNase I footprint analyses to bind the core site in the Moloney virus enhancer specifically, and also to core motifs in the enhancers from a simian immunodeficiency virus, the immunoglobulin mu chain, and T-cell receptor gamma-chain genes.

Base Sequence↗

PubMed2006

A fuzzy c-means (FCM)-based approach for computerized segmentation of breast lesions in dynamic contrast-enhanced MR images.

RATIONALE AND OBJECTIVES: Accurate quantification of the shape and extent of breast tumors has a vital role in nearly all applications of breast magnetic resonance (MR) imaging (MRI). Specifically, tumor segmentation is a key component in the computerized assessment of likelihood of malignancy. However, manual delineation of lesions in four-dimensional MR images is labor intensive and subject to interobserver and intraobserver variations. We developed a computerized lesion segmentation method that has the advantage of being automatic, efficient, and objective. MATERIALS AND METHODS: We present a fuzzy c-means (FCM) clustering-based method for the segmentation of breast lesions in three dimensions from contrast-enhanced MR images. The proposed lesion segmentation algorithm consists of six consecutive stages: region of interest (ROI) selection by a human operator, lesion enhancement within the selected ROI, application of FCM on the enhanced ROI, binarization of the lesion membership map, connected-component labeling and object selection, and hole-filling on the selected object. We applied the algorithm to a clinical MR database consisting of 121 primary mass lesions. Manual segmentation of the lesions by an expert MR radiologist served as a reference in the evaluation of the computerized segmentation method. We also compared the proposed algorithm with a previously developed volume-growing (VG) method. RESULTS: For the 121 mass lesions in our database, 97% of lesions were segmented correctly by means of the proposed FCM-based method at an overlap threshold of 0.4, whereas 84% of lesions were correctly segmented by means of the VG method. CONCLUSION: Our proposed algorithm for breast-lesion segmentation in dynamic contrast-enhanced MRI was shown to be effective and efficient.

Algorithms↗

PubMed2006

TMS orientation for NIRS-functional motor mapping.

Functional near-infrared spectroscopic imaging (NIRS imaging) has the potential to elucidate the relationship between neuronal activity and oxygenation responses. However, its signal specificity to the functional cortex is sometimes spoiled by its rough spatial resolution. In this study we incorporated transcranial magnetic stimulation (TMS) motor mapping into an NIRS imaging study to enhance spatial specificity to the functional cortex. Distinctive biphasic responses in the cortical oxygenation status were observed in the center of the primary motor cortex during a motor task. The early response phase, occurring within 1 to 3 seconds after task initiation, represents a cortical deoxygenation which consists of a significant increase in deoxygenated hemoglobin concentration (HbR) and a nonsignificant decreasing tendency in oxygenated hemoglobin concentration (HbO(2)). The delayed response phase represents an excess of incoming blood flow, which appears as an increase in HbO(2)/total Hb (tHb) and a decrease in HbR following the early response. In the surrounding area, cortical oxygenation change showed a monophasic response consisting of an increase in HbO(2)/tHb and a decrease in HbR. Combining TMS mapping with NIRS imaging enabled us to specify the cortex with the strongest functional activity.

Adult↗

PubMed1991

The Interleukin-6-dependent DNA-binding protein gene (transcription factor 5: TCF5) maps to human chromosome 20 and rat chromosome 3, the IL6 receptor locus (IL6R) to human chromosome 1 and rat chromosome 2, and the rat IL6 gene to rat chromosome 4.

Using two panels of somatic cell hybrids segregating either human or rat chromosomes, the gene encoding the interleukin-6-dependent DNA-binding protein, also called liver activator protein (designated transcription factor 5: TCF5), was assigned to human chromosome 20 and to rat chromosome 3. The TCF5 gene might be identical with the NF-IL6 gene. The locus encoding the IL6 receptor gene (IL6R) was localized to human chromosome 1 and rat chromosome 2. An IL6R-like (IL6RL) locus was also assigned to human chromosome 9. In addition, the rat interleukin-6 (IL6) gene was assigned to rat chromosome 4. These mapping data allow one to extend comparison between the rat, mouse, and human gene maps.

Animals↗

PubMed1999

PICKLE is a CHD3 chromatin-remodeling factor that regulates the transition from embryonic to vegetative development in Arabidopsis.

The life cycle of angiosperms is punctuated by a dormant phase that separates embryonic and postembryonic development of the sporophyte. In the pickle (pkl) mutant of Arabidopsis, embryonic traits are expressed after germination. The penetrance of the pkl phenotype is strongly enhanced by inhibitors of gibberellin biosynthesis. Map-based cloning of the PKL locus revealed that it encodes a CHD3 protein. CHD3 proteins have been implicated as chromatin-remodeling factors involved in repression of transcription. PKL is necessary for repression of LEC1, a gene implicated as a critical activator of embryo development. We propose that PKL is a component of a gibberellin-modulated developmental switch that functions during germination to prevent reexpression of the embryonic developmental state.

Arabidopsis↗

PubMed2002

Magnetic resonance imaging-guided laser thermal ablation of renal tumours.

OBJECTIVE: To test the hypothesis that magnetic resonance imaging (MRI)-guided laser thermal ablation (LTA) of inoperable renal tumours is a safe, tolerable and potentially effective treatment. PATIENTS AND METHODS: Nine patients (aged 56-81 years) with malignant renal tumours underwent percutaneous LTA under MRI guidance in a 0.5 T open magnet. Real-time colour thermal mapping was used to monitor tumour ablation, and the follow-up was with gadolinium-enhanced MRI at 6 weeks and (where appropriate) 3-4 months after the procedure. Tumour volume and percentage tumour enhancement before and after ablation were compared. The percentage of tumour ablated on real-time T1-weighted thermal maps was compared with that on gadolinium-enhanced follow-up MRI. RESULTS: The mean (range) follow-up was 16.9 (3-32) months after the first ablation. The mean tumour size did not change significantly, but the mean percentage of viable tumour decreased significantly from 73.7% before to 29.5% after ablation (P = 0.012, Wilcoxon signed-ranks test). Thermal maps correlated moderately well with follow-up MRI in predicting the extent of tumour ablation (Pearson correlation coefficient 0.55). There were two minor and one major complication. CONCLUSION: In this pilot study of patients unsuitable for surgery, MRI-guided LTA of renal tumours was safe, feasible (being well tolerated by the patient) and significantly reduced enhancing tumour volume by a mean of 45%.

Aged↗

PubMed2006

Determination of unique amino acid substitutions in protein variants by peptide mass mapping with FT-ICR MS.

Peptide mass mapping plays a central role in the structural characterization of protein variants with single amino acid substitutions. Among the 20 standard amino acids found in living organisms, 18, all but Leu and Ile, differ from each other in molecular mass. The mass differences between amino acids range from 0.0364 to 129.0578 Da. The mass of the mutated peptide or the difference between normal and mutated peptides uniquely determines the type of substitution in some cases, and even pinpoints the position of the mutation when the involved residue is found only once in the peptide. Among 75 pairs of amino acid residues that are exchangeable via a single nucleotide replacement, 53 show specific change in exact mass, while only 25 in nominal mass. On the other hand, precise measurement, at least to the third decimal place, greatly enhances the capacity of the peptide mass mapping strategy for structural characterization. This notion was verified by an analysis of three Hb variants using MALDI-FTICR MS. In addition, the baseline resolution of two 1 kDa peptides with a single amino acid difference, Lys or Gln, which have the smallest (0.0364 Da) difference among residues, was achieved by measurement at a mass resolving power of 342,000. The results indicated that the smallest difference, 0.0040 Da between [Delta29.9742 for Glu-Val] and [Delta29.9782 for Trp-Arg], among all types of amino acid substitutions derived from a single nucleotide replacement can be discriminated at the present performance level. Therefore, FTICR MS is capable of identifying all 53 types of substitutions, each of which is associated with a unique mass difference, except for the Leu and Ile isomers.

Amino Acid Sequence↗

PubMed1995

Binding sites for abundant nuclear factors modulate RNA polymerase I-dependent enhancer function in Saccharomyces cerevisiae.

The 190-base pair (bp) rDNA enhancer within the intergenic spacer sequences of Saccharomyces cerevisiae rRNA cistrons activates synthesis of the 35S-rRNA precursor about 20-fold in vivo (Mestel,, R., Yip, M., Holland, J. P., Wang, E., Kang, J., and Holland, M. J. (1989) Mol. Cell. Biol. 9, 1243-1254). We now report identification and analysis of transcriptional activities mediated by three cis-acting sites within a 90-bp portion of the rDNA enhancer designated the modulator region. In vivo, these sequences mediated termination of transcription by RNA polymerase I and potentiated the activity of the rDNA enhancer element. Two trans-acting factors, REB1 and REB2, bind independently to sites within the modulator region (Morrow, B. E., Johnson, S. P., and Warner, J. R. (1989) J. Biol. Chem. 264, 9061-9068). We show that REB2 is identical to the ABF1 protien. Site-directed mutagenesis of REB1 and ABF1 binding sites demonstrated uncoupling of RNA polymerase I-dependent termination from transcriptional activation in vivo. We conclude that REB1 and ABF1 are required for RNA polymerase I-dependent termination and enhancer function, respectively, Since REB1 and ABF1 proteins also regulate expression of class II genes and other nuclear functions, our results suggest further similarities between RNA polymerase I and II regulatory mechanisms. Two rDNA enhancers flanking a rDNA minigene stimulated RNA polymerase I transcription in a "multiplicative" fashion. Deletion mapping analysis showed that similar cis-acting sequences were required for enhancer function when positioned upstream or downstream from a rDNA minigene.

Amino Acid Sequence↗

PubMed2002

Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline.

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non-amyloidogenic a-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 mM) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via a-secretase activity. Using several signal transduction inhibitors, we identified the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism whereby these ChE inhibitors regulate the secretory processes of APP via activation of the MAP kinase pathway.

Amyloid beta-Protein Precursor↗

PubMed2003

Reproducibility of quantitative dynamic contrast-enhanced MRI in newly presenting glioma.

We have investigated the reproducibility of dynamic contrast enhanced imaging techniques in nine patients with cerebral glioma. Patients were imaged twice with a 2 day interval between scans. Maps were produced of the time taken to achieve 90% enhancement (T90), the maximal intensity change per time interval ratio (MITR), the volume transfer coefficient between plasma and the extravascular extracellular space (K(trans)) and the extravascular extracellular contrast distribution volume, v(e). Measurements of K(trans) greater than 1.2 min(-1) were used to exclude pixels where first pass perfusion effects dominated the measurement. Measures of the test-retest coefficient of variation (CoV) and intraclass correlation coefficients were used to assess reproducibility for measurements from a volume of interest containing enhancing tissue from the whole tumour. MITR showed poor reproducibility (mean CoV 17.9%, 95% confidence limits for group comparisons 20.2%). T90 showed good reproducibility (mean CoV 7.1%, 95% confidence limits for group comparisons 5.2%). Calculated values of K(trans) and v(e) also showed good reproducibility (mean CoV 7.7% and 6.2% respectively, 95% confidence limits for group comparisons 6.2% and 4.8%, respectively). We conclude that the measurements of K(trans) and v(e) derived from pharmacokinetic analysis are sufficiently reproducible to support their use as a biological markers in therapeutic trials.

Aged↗

PubMed1999

Influence of simulated microgravity on cardiovascular and hemodynamic parameters in Dahl salt-sensitive rats.

Prolonged exposure to microgravity, in humans, induces cardiovascular deconditioning and impairment of baroreflex activity partially as a result of fluid and electrolyte shifts. Animal models of simulated microgravity have been developed to mimic the above responses. We examined the effects of both 24 hr whole body suspension and 7 day tail-suspension and the subsequent 6 hr post-suspension in salt-loaded (2 wks on 8% NaCl diet) Dahl salt-sensitive rats. In both models, mean arterial pressure (MAP) and heart rate (HR) were unchanged during the suspension period. Upon release from suspension, there was no difference in the MAP or HR responses. Blood flows measured in the lower abdominal aorta and renal artery were not different between suspended and control animals. In both models, there was a similar body weight reduction in all groups. MAP responses to both phenylephrine (PHE) and sodium nitroprusside (SNP) were not affected by simulated microgravity. The HR response to SNP in suspended animals was greater than that of control animals; whereas, PHE-induced responses were not different. These data support the notion that simulated microgravity did not alter the MAP responses to SNP and PHE, however, HR responses were enhanced by SNP in the salt-loaded Dahl rats. In addition, salt-sensitivity/salt-loading prevents the reduction in MAP observed post-suspension in normotensive rats.

Animals↗

PubMed1987

Different functional sites on rIFN-alpha 2 and their relation to the cellular receptor binding site.

Functional domains on the recombinant interferon-alpha 2 (rIFN-alpha 2) molecule, which are involved in antiviral and NK enhancing activities, have been defined by immunochemical mapping with MAb, and their relationship with the IFN cellular receptor binding site has been studied. With 20 different anti-IFN-alpha 2 MAb selected by their binding to 125I-labeled IFN and by immunoprecipitation of the 20 Kd IFN molecule, we have defined three spatially separated epitopes (designated as sites A, B, and C) and two partially overlapping antigenic determinants on the IFN-alpha 2 molecule. Functional relation of IFN-alpha 2 A, B, and C epitopes have been determined by assaying the effect of various anti-IFN MAb on IFN-mediated biologic activities. MAb directed to sites A and B neutralized the antiviral activity of IFN. Furthermore, the MAb specific for site B displayed a neutralizing potency threefold higher than MAb directed to site A. Site B was also involved in the enhancing activity of IFN on NK-mediated cell cytotoxicity, whereas site A was not. MAb directed to site C partially affected the IFN-boosted NK activity but did not neutralize the IFN antiviral activity. Inhibition studies of 125I-IFN binding to human U-937 myelomonocytic cells by anti-IFN MAb demonstrated that MAb directed to site B blocked different IFN biologic functions by preventing its binding to the cellular receptor, whereas MAb directed to sites A and C caused no inhibition and partial inhibition of this binding, respectively.

Antibodies, Monoclonal↗

PubMed1996

Enhancement of dopamine release from the striatum through metabotropic glutamate receptor activation in methamphetamine sensitized rats.

An intracerebral microdialysis technique was applied to study the effect of metabotropic glutamate receptor (mGluR) agonist on dopamine release in the striatum of methamphetamine (MAP)-sensitized rats. Rats were treated with MAP (1 mg/kg, i.p.) once daily for 6 consecutive days, followed by a 6-day withdrawal. Perfusion of 0.1 mM (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid through a microdialysis probe placed in the striatum enhanced the extracellular dopamine level, and induced stereotyped behavior in MAP-sensitized rats. The enhancement of dopamine release and the stereotyped behavior were attenuated by co-perfusion of 0.4 mM RS-alpha-methyl-4-carboxyphenyl-glycine, a mGluR antagonist. The present results suggest that mGluRs may be involved in the expression of MAP-induced sensitization.

Animals↗

PubMed2003

In vivo assessment of macromolecular content in articular cartilage of the goat knee.

Loss of proteoglycans (PGs) from the extracellular matrix of cartilage is an early event of osteoarthritis. The capability of Gd(DTPA)(2-)-enhanced MRI to quantitatively assess PG content was explored in a goat model of cartilage degeneration. Partial to total PG depletion was induced by an intraarticular injection of papain 1 day prior to the MRI session. A close correlation was found between the extent of the PG loss and the Gd(DTPA)(2-)-induced T(1) decrease. Papain-induced PG depletion was confirmed by post-mortem histological and biochemical assessments. A 2-hr delay after Gd(DTPA)(2-) injection was found to be optimal for an accurate quantitation of the cartilage defect. A series of knee flexions were performed post-Gd(DTPA)(2-) injection to facilitate penetration of the contrast agent into cartilage. However, DeltaT(1)'s observed in cartilage of exercised goat knees were not affected by papain or IL1beta pretreatment. Therefore, as long as a preinjection T(1) map was obtained, the Gd(DTPA)(2-)-enhanced MRI technique provided good sensitivity in detecting partial loss of PG in articular cartilage. This was true only when the animal was maintained in a resting state during diffusion of the Gd(DTPA)(2-). This approach is of particular interest for long-term evaluations of cartilage degeneration and regeneration.

Animals↗

PubMed1997

The tripartite basal enhancer of the gonadotropin-releasing hormone (GnRH) receptor gene promoter regulates cell-specific expression through a novel GnRH receptor activating sequence.

The molecular mechanisms regulating restricted expression of GnRH receptor and gonadotropin subunit genes to gonadotrope cells have been the focus of intense interest. Using deletion and mutational analysis we have identified a tripartite enhancer that regulates cell-specific expression of the GnRH receptor gene in the gonadotrope-derived alphaT3-1 cell line. Individual elements of this enhancer include binding sites for steroidogenic factor-1; activator protein 1 (AP-1); and a novel element referred to as the GnRH receptor activating sequence (GRAS). Mutation of each element alone results in loss of approximately 60% of promoter activity. Combinatorial mutations of any two elements decreases promoter activity by approximately 80%. Finally, mutation of all three elements reduces promoter activity to a level not different from promoterless vector. Using 2-bp mutations, we have defined the functional requirements for transcriptional activation by GRAS. The core motif of GRAS is at -391 to -380 bp relative to the start site of translation and has the sequence 5'-CTAGTCACAACA-3'. Three copies of GRAS or GRAS with a 2-bp mutation (muGRAS) were cloned into a luciferase expression vector immediately upstream of the thymidine kinase minimal promoter (TK) and tested for expression in alphaT3-1 cells. When compared with TK promoter alone, activity of 3xGRAS-TKLUC was increased by more than 5-fold while activity of 3xmuGRAS-TKLUC was unchanged. When 3xGRAS-TKLUC was transfected into a variety of nongo-nadotrope cell lines, it did not increase activity of the TK promoter. We propose that basal activity of the GnRH receptor gene is regulated by a tripartite enhancer, and the key component of this enhancer is an element, GRAS, that activates transcription in a cell-specific fashion.

Animals↗