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Results for “Gene Expression”

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PubMed2003

Extracting conserved gene expression motifs from gene expression data.

We propose a representation for gene expression data called conserved gene expression motifs or XMOTIFs. A gene's expression level is conserved across a set of samples if the gene is expressed with the same abundance in all the samples. A conserved gene expression motif is a subset of genes that is simultaneously conserved across a subset of samples. We present a computational technique to discover large conserved gene motifs that cover all the samples and classes in the data. When applied to published data sets representing different cancers or disease outcomes, our algorithm constructs XMOTIFS that distinguish between the various classes.

Algorithms↗

PubMed2002

Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.

The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expression databases that benefit from coherent data sets, and which are constructed to facilitate a particular analytic method, but rather complement these by acting as a tertiary, central data distribution hub. The three central data entities of GEO are platforms, samples and series, and were designed with gene expression and genomic hybridization experiments in mind. A platform is, essentially, a list of probes that define what set of molecules may be detected. A sample describes the set of molecules that are being probed and references a single platform used to generate its molecular abundance data. A series organizes samples into the meaningful data sets which make up an experiment. The GEO repository is publicly accessible through the World Wide Web at http://www.ncbi.nlm.nih.gov/geo.

Animals↗

PubMed2006

Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells.

PURPOSE: As a follow-up to our previous findings that platinum drugs induce a key enzyme in polyamine catabolism, gene expression profiling and mathematical modeling were used to define the effects of cisplatin and oxaliplatin on the expression of polyamine metabolic pathway genes in A2780 human ovarian carcinoma cells. METHODS: Time-course and concentration-effect experiments were each carried out with cisplatin or oxaliplatin in two separate experiments and cells subjected to gene expression profiling using Affymetrix array technology. Time-course data were modeled using exponential increase and decrease models. Concentration-effect data were modeled using a four parameter Hill model. RESULTS: Gene expression profiling of human ovarian carcinoma A2780 cells after exposure to either cisplatin or oxaliplatin indicates that the expression of several genes involved in polyamine pathway is affected by the platinum drugs. Mathematical/Statistical modeling of the data from time-course and concentration-effect experiments of gene expression from nine polyamine pathway genes represented on the HGU95Av2 chip, indicates that three biosynthetic pathway genes (SAMDC, ODC1 and SRM) are down-regulated and one catabolic pathway gene (SSAT) is up-regulated. Expression changes were similar for different probesets for a given gene on the array. Studies on the induction of SSAT by platinum drugs suggested by the Affymetrix data have been previously validated from this laboratory (Hector et al. in Mol Cancer Ther 3:813-822, 2004). Here, the effects of oxaliplatin exposure on SAMDC and ODC observed by Affymetix are validated with real time QRT-PCR. CONCLUSION: The data indicate a concerted effect of platinum drugs on the polyamine metabolic pathway with down-regulation in the expression of several enzyme genes involved in biosynthesis and many-fold up-regulation in expression of SSAT, an acetylating enzyme gene that is critically involved in polyamine catabolism and export.

Acyltransferases↗

PubMed2003

Endometrial effects of selective estrogen receptor modulators (SERMs) on estradiol-responsive gene expression are gene and cell-specific.

Three selective estrogen receptor modulator (SERM) drugs which included 4-OH-tamoxifen (Tam), EM-800 (EM) and GW 5638 (GW) were investigated to determine their ability to inhibit estradiol-responsive gene expression in sheep endometrium. The uteri of ovariectomized ewes (10 ewes per SERM group) were infused with 10(-7)M SERMs for 24h prior to hysterectomy. Five ewes from each group received 50 microg 17beta-estradiol (E2) and the remaining five ewes received vehicle 18 h prior to hysterectomy. Northern blot analyses and in situ hybridization demonstrated that E2 treatment increased estrogen receptor (ER), progesterone receptor (PR), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and cyclophilin (CYC) mRNA levels in most endometrial cells examined. Tam and GW exhibited characteristics similar to E2 by increasing ER gene expression, but they antagonized the E2-induced increases in PR and CYC mRNA levels. EM acted as an E2-agonist of GAPDH gene expression, but antagonized the E2 up-regulation of ER, PR and CYC gene expression in most endometrial cells. Immunohistochemistry determined that EM decreased ER protein levels in the glandular epithelium, and the SERMs investigated antagonized increases in PR protein levels in endometrium. In conclusion, GW and EM exhibit fewer agonist effects than Tam on endometrial gene expression. EM demonstrated the greatest antagonism of E2-enhanced levels of ER, PR and CYC, likely due to the inhibition of ER gene expression at both mRNA and protein levels.

Animals↗

PubMed2005

Gene expression evolves faster in narrowly than in broadly expressed mammalian genes.

Despite much recent interest, it remains unclear what determines the rate of evolution of gene expression. To study this issue we develop a new measure, called "Expression Conservation Index" (ECI), to quantify the degree of tissue-expression conservation between two homologous genes. Applying this measure to a large set of gene expression data from human and mouse, we show that tissue expression tends to evolve rapidly for genes that are expressed in only a limited number of tissues, whereas tissue expression can be conserved for a long time for genes expressed in a large number of tissues. Therefore, expression breadth is an important determinant for evolutionary conservation of tissue expression. In addition, we find a rapid decrease in ECI with the synonymous divergence between duplicate genes, suggesting fast divergence in tissue expression between duplicate genes.

Animals↗

PubMed1996

A humanized system for pharmacologic control of gene expression.

Gene therapy was originally conceived as a medical intervention to replace or correct defective genes in patients with inherited disorders. However, it may have much broader potential as an alternative delivery platform for protein therapeutics, such as cytokines, hormones, antibodies and novel engineered proteins. One key technical barrier to the widespread implementation of this form of therapy is the need for precise control over the level of protein production. A suitable system for pharmacologic control of therapeutic gene expression would permit precise titration of gene product dosage, intermittent or pulsatile treatment, and ready termination of therapy by withdrawal of the activating drug. We set out to design such a system with the following properties: (1) low baseline expression and high induction ratio; (2) positive control by an orally bioavailable small-molecule drug; (3) reduced potential for immune recognition through the exclusive use of human proteins; and (4) modularity to allow the independent optimization of each component using the tools of protein engineering. We report here the properties of this system and demonstrate its use to control circulating levels of human growth hormone in mice implanted with engineered human cells.

Animals↗

PubMed2005

[Gene expression profiling of peripheral leukocytes from patients with systemic lupus erythematosus using oligonucleotide DNA microarray].

OBJECTIVE: To identify the differentially expressed genes in systemic lupus erythematosus (SLE) by comparing the gene expression profiles of peripheral leukocytes between SLE patients and healthy controls. METHODS: The total RNA was extracted from 5 ml peripheral blood of normal subjects and SLE patients, and reversely transcribed in cDNA templates to synthesize cDNA probes labeled for hybridization with the microarray. RESULTS: Totally 89 over- or under-expressed genes were identified in 9 SLE patients as compared with the controls. These genes included genes associated with cytokines and their receptors, immunity, cell signal transduction, protein transcription and synthesis, ion channel and transporters, cell apoptosis, DNA and RNA processing, and extracellular matrix etc. Clustering analysis showed that in spite of the individual diversity of the SLE patients, their gene expression profiles were strikingly similar. CONCLUSION: The differentially expressed genes screened with oligonucleotide DNA microarray technique may provide clues for exploring the pathogenesis and progression of SLE, and for identification of potential molecular markers for diagnosis and development of therapeutic drugs.

Adult↗

PubMedDate not supplied

Gene expression and gene therapy in experimental duodenal ulceration.

Gastroduodenal ulceration is still poorly understood and changes in gene expression may provide new mechanistic insights. Previously, we demonstrated that angiogenic growth factors are potent ulcer healing agents, and the synthesis of bFGF, PDGF and VEGF is enhanced early in duodenal ulcer healing. The initial molecular event in duodenal ulceration seems to be the organ-specific early release of ET-1 in the pre-ulcerogenic stages after the administration of duodenal ulcerogen cysteamine in rats. We also briefly review here data from literature indicating a central role of ET-1 in gastroduodenal ulceration. After studying the involvement of immediate early genes (e.g. egr-1, Sp1) in ulcer development, we now investigated expression of other genes in the duodenal mucosa in the early stages of chemically induced duodenal ulceration in rats. Following a brief review of principles of gene expression and gene therapy, we review our preliminary gene expression studies, involving monitoring about 1200 genes which revealed about 160 signals and prominent changes in about 30 genes in the early stages of experimental duodenal ulceration. Cysteamine enhanced ET-B receptor gene expression in 30 min, while transcription factors (MAX, STAT 3) showed increased expression in 12 h. We recently also initiated gene therapy studies to enhance the local synthesis of PDGF and VEGF to accelerate duodenal ulcer healing, using a single dose of naked DNA (ND) or adenoviral (AV) vectors of VEGF and PDGF in rats with cysteamine-induced duodenal ulcers. Gene therapy with ND or AV of VEGF or PDGF significantly accelerated chronic duodenal ulcer healing, and increased levels of VEGF and PDGF were detected by Western blotting and ELISA in duodenal mucosa after both VEGF and PDGF gene therapy. Thus, gene expression studies provide new insights into the molecular mechanisms of duodenal ulceration and VEGF or PDGF gene therapy seems to be a new option to achieve a rapid ulcer healing.

Animals↗

PubMed2004

[The gene expression patterns of genetic P77PMC epilepsy-prone rats' hippocampus].

OBJECTIVE: To find out the differentially expressed genes in the hippocampus of the rats with genetic epilepsy so as to lay a foundation for exploring the pathogenesis of epilepsy by means of cDNA array technology. METHODS: Gene expression patterns in the hippocampus of the genetic epilepsy-prone P77PMC rats and normal Wistar rats were established using the alpha-32P-labeled cDNA probes hybridized with the Atlas Rat cDNA Expression Array, and then were analyzed by an image analysis instrument to get the differentially expressed genes. RESULTS: Fifteen genes were found having differential expression patterns in hippocampus between the P77PMC rats and the Wistar rats, while there may be many other differentially expressed genes left undiscovered due to having no appropriate image analysis software. And among the fifteen genes, the expression levels of twelve genes in the P77PMC rats were higher than those in the Wistar rats, while the expression levels of the other three genes were lower. The results of reverse transcription-polymerase chain reaction(RT-PCR) have demonstrated the reliability of cDNA arrays method. CONCLUSION: cDNA array is a powerful tool for identifying differential expression genes of epilepsy on large scales. There are several differentially expressed genes in hippocampus of the P77PMC rats and the Wistar rats. All these identified genes could play potentially important roles in the pathogenesis of epilepsy.

Animals↗

PubMed2006

CoXpress: differential co-expression in gene expression data.

BACKGROUND: Traditional methods of analysing gene expression data often include a statistical test to find differentially expressed genes, or use of a clustering algorithm to find groups of genes that behave similarly across a dataset. However, these methods may miss groups of genes which form differential co-expression patterns under different subsets of experimental conditions. Here we describe coXpress, an R package that allows researchers to identify groups of genes that are differentially co-expressed. RESULTS: We have developed coXpress as a means of identifying groups of genes that are differentially co-expressed. The utility of coXpress is demonstrated using two publicly available microarray datasets. Our software identifies several groups of genes that are highly correlated under one set of biologically related experiments, but which show little or no correlation in a second set of experiments. The software uses a re-sampling method to calculate a p-value for each group, and provides several methods for the visualisation of differentially co-expressed genes. CONCLUSION: coXpress can be used to find groups of genes that display differential co-expression patterns in microarray datasets.

Algorithms↗

PubMed2005

A capsid-modified helper-dependent adenovirus vector containing the beta-globin locus control region displays a nonrandom integration pattern and allows stable, erythroid-specific gene expression.

Gene therapy for hemoglobinopathies requires efficient gene transfer into hematopoietic stem cells and high-level erythroid-specific gene expression. Toward this goal, we constructed a helper-dependent adenovirus vector carrying the beta-globin locus control region (LCR) to drive green fluorescent protein (GFP) expression, whereby the LCR-GFP cassette is flanked by adeno-associated virus (AAV) inverted terminal repeats (Ad.LCR-beta-GFP). This vector possesses the adenovirus type 35 fiber knob that allows efficient infection of hematopoietic cells. Transduction and vector integration studies were performed in MO7e cells, a growth factor-dependent CD34(+) erythroleukemic cell line, and in cord blood-derived human CD34(+) cells. Stable transduction of MO7e cells with Ad.LCR-beta-GFP was more efficient and less subject to position effects and silencing than transduction with a vector that did not contain the beta-globin LCR. Analysis of integration sites indicated that Ad.LCR-beta-GFP integration in MO7e cells was not random but tethered to chromosome 11, specifically to the globin LCR. More than 10% of analyzed integration sites were within the chromosomal beta-globin LCR. None of the Ad.LCR-beta-GFP integrations occurred in exons. The integration pattern of a helper-dependent vector that contained X-chromosomal stuffer DNA was different from that of the beta-globin LCR-containing vector. Infection of primary CD34(+) cells with Ad.LCR-beta-GFP did not affect the clonogenic capacity of CD34(+) cells. Transduction of CD34(+) cells with Ad.LCR-beta-GFP resulted in vector integration and erythroid lineage-specific GFP expression.

Adenoviridae↗

PubMed2005

Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development.

Gene expression patterns in ductal carcinoma in situ (DCIS) and invasive and metastatic breast tumors have been determined using serial analysis of gene expression (SAGE). The purpose of this approach was to identify biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease. The analyses have led to the identification of several differentially expressed genes, such as HIN-1, dermcidin and S100A7 (psoriasin). The aim of the present study was further to delineate the expression profile of S100 genes using information from 22 breast epithelial SAGE libraries. We demonstrated the down-regulation of S100A6 and S100A10 in breast cancer, irrespective of pathological stage. S100P and S100Z were both up-regulated in cancer; whereas S100A7, S100A8 and S100A9 were strongly up-regulated only in DCIS. The hierarchical clustering of S100 gene expression in these 22 libraries revealed two major groups with distinguishable S100 gene expression profiles. One of them was characterized by the high concomitant expression of S100A7, S100A8 and S100A9. Using SAGE informatics, we found 21 genes with a high positive correlation to S100A7 expression in libraries representing different categories of tissues archived at SAGE Genie, suggesting a function of psoriasin that is not tissue specific. Like S100A7, several of these genes displayed cation-binding properties. We also report the strong correlation in the breast epithelial SAGE libraries between the expression of S100A7 and genes reported as being up-regulated in DCIS, as well as in the inflammatory skin disorder, psoriasis; including RGS5, UPK1A, TMPRSS3, S100A9, p53, SCCA1, SCCA2 and KRT17.

Base Sequence↗

PubMed2001

Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas.

In clinical gene-therapy trials for recurrent glioblastomas, transduction of the herpes simplex virus type-1 thymidine kinase (HSV-1-tk) gene with subsequent prodrug activation by ganciclovir was found to be safe, but clinical response was poor. We used positron-emission tomography (PET) with I-124-labelled 2'-fluoro-2'-deoxy-1b-D-arabino-furanosyl-5-iodo-uracil ([124I]-FIAU)-a specific marker substrate for gene expression of HSV-1-tk-to identify the location, magnitude, and extent of vector-mediated HSV-1-tk gene expression in a phase I/II clinical trial of gene therapy for recurrent glioblastoma in five patients. The extent of HSV-1-tk gene expression seemed to predict the therapeutic response. The expression of an exogenous gene introduced by gene therapy into patients with gliomas can be monitored non-invasively by PET.

Aged↗

PubMed2002

Specific interference with gene expression and gene function mediated by long dsRNA in neural cells.

Double-stranded (ds) RNA-induced sequence-specific interference with gene expression, RNA interference (RNAi), has been extensively used in invertebrates, allowing for efficient and high-throughput gene silencing and gene function analysis. In vertebrates, however, use of RNAi to study gene function has been limited due to non-specific effects induced by double-stranded RNA (dsRNA)-dependent protein kinase and interferon activation. dsRNA-induced specific inhibition of vertebrate gene expression has only been shown in embryonic and non-differentiated mammalian cells. In this report, we demonstrate dsRNA-induced specific interference of gene expression and gene function in partially as well as fully differentiated mouse neuroblastoma cells. Specific silencing was observed in the expression of an integrated transgene coding for green fluorescent protein and a variety of endogenous genes. Moreover, we show that RNAi-mediated inhibition of poly (ADP-ribose) polymerase (PARP) expression induced cellular resistance to oxygen-glucose deprivation, consistent with the role of PARP in ischemia-induced brain damage. Our results indicate that RNAi can be used as a powerful tool to study gene function in neural cells.

Animals↗

PubMed2003

System for simultaneous tissue-specific and disease-specific regulation of therapeutic gene expression.

Gene therapy has been proposed as an alternative strategy for treating nongenetic disorders, such as cancer and coronary artery disease. However, for many of these types of diseases, the therapeutic genes must be tightly regulated, as extensive toxicity and pathology can result if their expression is not adequately controlled. Toward this end, we have developed a regulatory system in which the expression of a therapeutic transgene is controlled simultaneously by both a tissue-specific promoter and a disease-specific promoter. Thus, the transgene of interest will be expressed in a given cell only if both of these promoters are active. Unlike many other transgene-regulatory systems that have been previously developed, this system does not require the persistent expression of any foreign genes that could provoke an immune response or lead to toxicity. As proof of concept, we synthesized a construct harboring the lacZ transgene that is under the control of both the hepatocyte-specific human alpha(1)-antitrypsin promoter and the zinc-inducible mouse metallothionein promoter. We show that reporter gene expression from this construct is regulated in both a hepatocyte-specific and zinc-regulated manner, as reporter gene expression occurs only in hepatocyte-derived cells that have been exposed to zinc. The improved regulation offered by our system would facilitate the targeting of transgene expression to sites of disease in the body and spare healthy tissue, thereby considerably enhancing the therapeutic window of gene therapy.

DNA Primers↗

PubMed2003

The genetics of gene expression and gene mapping.

A recent publication has shown that a significant portion of gene expression levels are under genetic control in different organisms, that there are hotspot regions in the genome that control the expression of many other genes, and how gene expression data can be used to localize genes that affect clinical traits.

Adipose Tissue↗

PubMed2006

Normalization and quantification of differential expression in gene expression microarrays.

Array-based gene expression studies frequently serve to identify genes that are expressed differently under two or more conditions. The actual analysis of the data, however, may be hampered by a number of technical and statistical problems. Possible remedies on the level of computational analysis lie in appropriate preprocessing steps, proper normalization of the data and application of statistical testing procedures in the derivation of differentially expressed genes. This review summarizes methods that are available for these purposes and provides a brief overview of the available software tools.

Algorithms↗

PubMed2000

Serial analysis of gene expression: from gene discovery to target identification.

Serial Analysis of Gene Expression (SAGE) is a sequence-based genomics tool that features comprehensive gene discovery and quantitative gene expression capabilities. As an 'open' system, SAGE can reveal which genes are expressed and their level of expression rather than merely quantifying the expression level of a predetermined, and presently incomplete, set of genes as carried out by 'closed' system gene expression profiling platforms such as microarrays. These distinguishing attributes enable SAGE to be used as a primary discovery engine that can characterize human disease at the molecular level while illuminating potential targets and markers for therapeutic and diagnostic development, respectively.

Journal Article↗