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PubMed2002

Massively parallel signature sequencing (MPSS) as a tool for in-depth quantitative gene expression profiling in all organisms.

Massively parallel signature sequencing (MPSS) is one of the newest tools available for conducting in-depth expression profiling. MPSS is an open-ended platform that analyses the level of expression of virtually all genes in a sample by counting the number of individual mRNA molecules produced from each gene. There is no requirement that genes be identified and characterised prior to conducting an experiment. MPSS has a routine sensitivity at a level of a few molecules of mRNA per cell, and the datasets are in a digital format that simplifies the management and analysis of the data. Therefore, of the various microarray and non-microarray technologies currently available, MPSS provides many advantages for generating the type of complete datasets that will help to facilitate hypothesis-driven experiments in the era of digital biology.

Cloning, Molecular↗

PubMed2006

[Gene expression profiling for prediction of response to chemotherapy].

Numerous genes whose expression is controlled by complex regulatory networks are involved in the development and progression of each cancer,and those genes will be the key factors for determining each characteristic of the tumor. The recent development of DNA microarray and related technologies provides an opportunity to perform more detailed characterization( profiling) of individual tumor cells. Indeed, the gene expression profile of a tumor provides a unique molecular portrait or signature that can be correlated with clinical behavior and drug responsiveness. The development of personalized( or customized) medicine and molecularly targeted drugs is enthusiastically awaited based on the results of research examining genomic diversity such as SNPs( single nucleotide polymorphisms), gene expression profiling with DNA microarrays, and analysis of protein expression and interactions.

Antineoplastic Agents↗

PubMed2004

Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts.

The interactions between cancer cells and surrounding stroma play a critical role in tumor progression, but their molecular basis is largely unknown. Global gene expression profiling was performed using oligonucleotide microarrays to determine changes in the gene expression of pancreatic cancer cells (CFPAC1) and stromal fibroblasts induced by coculture. This analysis identified multiple genes as differentially expressed in pancreatic cancer cells and in fibroblasts as a consequence of their mutual interactions, including those that encode for proteins associated with tumor invasion, metastasis, and angiogenesis. Among the genes identified, the cyclooxygenase-2 (COX-2)/PTGS2 gene was of particular interest because COX-2 expression was markedly augmented in both cell types (cancer cells and fibroblasts) in response to coculture. Coculture with fibroblasts also induced COX-2 expression in additional pancreatic cancer cells with an unmethylated COX-2 promoter, but not in those with a methylated COX-2 promoter. Using an in vitro invasion assay, we found an increase in the invasive potential of CFPAC1 cells when they were cocultured with fibroblasts, an effect blocked partially by the addition of a selective COX-2 inhibitor, NS-398, or by COX-2 knockdown with small interfering RNA. Thus, COX-2 inhibitors can decrease the invasive properties of pancreatic cancer cells acquired through tumor-stromal interactions.

Cell Communication↗

PubMed2000

Individual variation in the expression profiles of nicotinic receptors in the olfactory bulb and trigeminal ganglion and identification of alpha2, alpha6, alpha9, and beta3 transcripts.

Nicotine evokes dose-dependent and often variable chemosensory responses in animals and humans. Earlier observations that nicotine binds to some nicotinic acetylcholine receptor (nAChR) subtypes in the olfactory bulb (OB) and trigeminal ganglion (TG) led us to investigate the complete nAChR expression profile in each tissue and to determine whether inter-individual differences exist in male and female rats. Total RNA was extracted from individual samples of dissected OB and TG and analyzed by a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay to determine the messenger RNA profiles of ten transcripts encoded by the alpha2, alpha3, alpha4, alpha5, alpha6, alpha7, alpha9, beta2, beta3, and beta4 nAChR genes. We found that (a) in the OB, all animals expressed alpha2, alpha3, alpha4, alpha5, alpha7, beta2, and beta4 subunit mRNAs, whereas alpha6, beta3, and alpha9 transcripts were expressed in only 17, 28, and 33% of the animals, respectively, and (b) in the TG, all animals expressed alpha2, alpha3, alpha6, alpha7, beta2, and beta4 subunit mRNAs, whereas alpha9, beta3, alpha4, and alpha5 transcripts were expressed in 4, 38, 88, and 92% of the animals, respectively. These results also identified new subunits that are expressed in each tissue (alpha2, alpha6, alpha9, and beta3) and demonstrated that individual rats may have different tissue-specific expression profiles for alpha4, alpha5, alpha6, alpha9, and beta3 transcripts. Such variations are likely to be reflected in the composition of functional receptor subtypes in the rat OB and TG that have different activation and desensitization characteristics to acetylcholine and nicotine.

Acetylcholine↗

PubMed2006

Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase.

We have used gene expression profiling to characterize genes regulated by the anti-tumor non-steroidal anti-inflammatory drug (NSAID)-like agent R-flurbiprofen (RFB) in murine TRAMP prostate cancer. Mice with spontaneous, palpable tumors were treated with RFB 25 mg/(kgd) x 7d orally, or vehicle only. RNA was then extracted from tumor tissue and used for microarray analysis with Affymetrix chips. Fifty-eight genes were reproducibly regulated by RFB treatment. One of the most highly up-regulated genes was prostate stem cell antigen (psca). We used TRAMP C1 murine prostate cancer cells to examine potential mechanisms through which RFB could regulate psca. RFB induced dose-dependent expression of PSCA protein, and activity of the psca promoter, in TRAMP C1 cells in culture. Increased psca promoter activity was also seen following treatment of cells with sulindac sulfone, another NSAID-like agent, but not with celecoxib treatment. RFB activation of the psca promoter could be attenuated by co-transfection of dominant-negative akt and h-ras constructs, but not by dominant-negative mek1 plasmids. Immunoblotting revealed that RFB increased expression of phosphorylated AKT at concentrations that stimulated psca promoter activity, and that increased PSCA protein expression. In addition, RFB-dependent up-regulation of PSCA protein expression could be blocked by AKT inhibitors. These data demonstrate that RFB, and possibly other NSAID-like analogs, can increase expression of the psca gene both in vivo and in culture. They further suggest the utility of combining RFB with AKT inhibitors or with monoclonal antibodies targeting PSCA protein, for treatment or prevention of prostate cancer.

Animals↗

PubMed2002

Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes.

The gene expression profile induced by the CC chemokine ligand (CCL) 5/RANTES in human monocytes was examined using the oligonucleotide array technology. Of 5600 transcripts examined, 42 were consistently induced by CCL5, and none were suppressed. Chemokine-inducible transcripts could be clustered in functional groups, including selected cytokines and receptors (e.g., IL-1beta, CCL2/monocyte chemotactic protein-1, and the CCL5 receptor CCR1) and molecules involved in extracellular matrix recognition and digestion (e.g., CD44 splice transcripts, urokinase-type plasminogen activator receptor, matrix metalloprotease (MMP)-9, and MMP-19). Transcript expression, confirmed by quantitative real-time PCR analysis for selected genes, was associated with protein induction for some (e.g., CCL2), but not all (e.g., IL-1beta), transcripts examined. The chemokine-induced gene profile was distinct from that activated by LPS, a prototypic phagocyte activator. Although certain transcripts were stimulated by both agonists (e.g., IL-1beta and CCL2), others were induced only by either LPS (e.g., TNF-alpha and IL-6) or CCL5 (e.g., MMP-19) or were divergently regulated (e.g., CCR1). Thus, CCL5, a prototypic CC inflammatory chemokine, activates a restricted transcriptional program in monocytes distinct from that induced by the prototypic pathogen-derived proinflammatory stimulant LPS. Chemokine-induced chemokines production could represent a novel amplification loop of leukocyte recruitment, while a subset of chemokine-inducible transcripts could be involved in monocyte extravasation and tissue invasion.

Chemokine CCL5↗

PubMed2003

Comparison of the gene expression profiles of monocytic versus granulocytic lineages of HL-60 leukemia cell differentiation by DNA microarray analysis.

It is now recognized that precise patterns of differentially expressed genes ultimately direct a particular cell toward a given lineage. In this study, we compared the expression profiles of cancer-related genes by cDNA microarray analysis during the differentiation of human promyelocytic leukemia HL-60 cells into either monocytes or granulocytes. RNA was isolated at times 0, 6, 12, 24, 36, 48, and 72 h following stimulation of differentiation with all-trans retinoic acid (all-trans RA) or 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], and hybridized to the microarray gene chips containing 872 genes related to cell-cycles, oncogenes and leukemias. Several genes were commonly or differentially regulated during cell differentiation into either lineage, as demonstrated by both hierarchical and self-organizing map clustering analysis. At 72 h the expression levels of 45 genes were commonly up- or down-regulated at least a twofold in both lineages. Most importantly, 32 genes including alpha-L-fucosidase gene and adducin gamma subunit gene were up- or down-regulated only in all-trans RA-treated HL-60 cells, while 12 genes including interleukin 1beta and hypoxia-inducible factor 1alpha were up- or down-regulated only in 1,25-(OH)(2)D(3)-treated HL-60 cells. The expression of selected genes was confirmed by Northern blot analysis. As expected, some genes identified have not been examined during HL-60 cell differentiation into either lineage. The identification of genes associated with a specific differentiation lineage may give important insights into functional and phenotypic differences between two lineages of HL-60 cell differentiation.

Calcitriol↗

PubMed2005

Analysis of the female gametophyte transcriptome of Arabidopsis by comparative expression profiling.

The extensive data on the transcription of the plant genome are derived primarily from the sporophytic generation. There currently is little information on genes that are expressed during female gametophyte development in angiosperms, and it is not known whether the female gametophyte transcriptome contains a major set of genes that are not expressed in the sporophyte or whether it is primarily a subset of the sporophytic transcriptome. Because the embryo sac is embedded within the maternal ovule tissue, we have utilized the Arabidopsis (Arabidopsis thaliana) mutant sporocyteless that produces ovules without embryo sacs, together with the ATH1 Arabidopsis whole-genome oligonucleotide array, to identify genes that are preferentially or specifically expressed in female gametophyte development. From analysis of the datasets, 225 genes are identified as female gametophyte genes, likely a lower limit as stringent criteria were used for the analysis, eliminating many low expressed genes. Nearly 45% of the identified genes were not previously detected by sporophytic expression profiling, suggesting that the embryo sac transcriptome may contain a significant fraction of transcripts restricted to the gametophyte. Validation of six candidate genes was performed using promoterbeta-glucuronidase fusions, and all of these showed embryo sac-specific expression in the ovule. The unfiltered expression data from this study can be used to evaluate the possibility of female gametophytic expression for any gene in the ATH1 array, and contribute to identification of the functions of the component of the Arabidopsis genome not represented in studies of sporophytic expression and function.

Arabidopsis↗

PubMed2003

Selection of surrogate marker genes in primary central nervous system lymphomas for radio-chemotherapy by DNA array analysis of gene expression profiles.

Primary central nervous system lymphomas (PCNSLs) are extra nodal B-cell non-Hodgkin's lymphomas with primary manifestation in the brain, and their incidence has been increasing among both immunocompetent and immunocompromised populations. Samples of oligodendroglioma (n=5), glioblastoma (n=7), PCNSL (n=6), and normal brain (n=3) were studied (total of 21 samples) using cDNA array technology. The hierarchical clustering algorithm was used to obtain a phylogenetic tree, and it revealed a striking feature: PCNSL was clearly separated. The genes encoding laminin receptor 2, thioredoxin peroxidase, and elongation factor-1 were selected as specific genes in PCNSL by principal component analysis (PCA). When Mann-Whitney tests were performed to identify genes responsible for the differences between responders and non-responders to the treatment schedule for PCNSL, 76 known genes were found to show significantly different expression patterns between the two groups at the P<0.01 level. The two groups were clearly separated by the re-clustering method using the selected genes related to response to chemo-radiotherapy. This is the first report describing the gene expression profiles of PCNSL. In conclusion, accumulation of data with respect to the expression profiles of PCNSL specimens, clinicopathological data, susceptibility to treatment, and outcome will provide information for identifying optimal therapeutic modalities for individual patients and novel therapeutic targets.

Adult↗

PubMedDate not supplied

Identification of novel ethanol-sensitive genes by expression profiling.

Chronic exposure to ethanol or other addicting drugs causes long-lasting, deleterious behavioral responses, such as tolerance, dependence, sensitization, and addiction. Changes in brain gene expression are thought to be a critical component of these behavioral adaptations. Our laboratory and others have utilized cultured neuronal cells as model systems for studying gene regulation by ethanol. Recently, the use of non-biased, high-throughput approaches to studying gene expression has allowed identification of gene regulation "patterns," rather than single genes responding to ethanol. This review will discuss how expression-profiling approaches can be used to identify functional changes occurring in neural cells with chronic exposure to ethanol.

Central Nervous System Depressants↗

PubMed2003

Gene expression profile of endothelin-1-induced growth in glomerular mesangial cells.

Endothelin (ET)-1 is a vasoconstrictor and mitogen involved in vascular remodeling. Changes in gene expression that underlie control of cell growth by ET-1 remain poorly characterized. To identify pathways of growth control we used microarrays to analyze ET-1-regulated gene expression in human mesangial cells, an important ET-1 vascular target cell in vivo. Statistical assessment of differential expression (significance analysis of microarrays) revealed upregulated transcripts for growth factors [heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), fibroblast growth factor (FGF), interleukin (IL)-6] and downregulated transcripts for genes that inhibit growth (BAX, p27KIP1, DAD1). Consistent with the gene expression profile, quantitative RT-PCR and Western blotting confirmed induction of HB-EGF by ET-1. To test a functional role for HB-EGF in ET-1 signaling, we showed that exogenous HB-EGF stimulated phosphorylation of ErbB1 and growth of mesangial cells. ET-1-induced proliferation was blocked by an ErbB1 receptor-selective kinase inhibitor and by a specific ErbB1 receptor-neutralizing antibody. Proliferation in response to ET-1 was also inhibited by neutralizing antisera against human HB-EGF. Together, these results provide data for modeling ET-1 pathways for growth control and suggest a specific role for HB-EGF gene induction in mesangial cell growth in response to ET-1.

Cell Division↗

PubMed2006

Establishment of cell lines that exhibit correct ontogenic stage-specific gene expression profiles from tissues of yeast artificial chromosome transgenic mice using chemically induced growth signals.

Transgenic mice produced with human yeast artificial chromosomes (YACs) generally display transgene expression patterns that reflect those of the normal human host. Because mice are expensive and time-consuming to generate and maintain, extensive mutation-phenotype correlation studies cannot be readily carried out. Cell lines are better suited for analysis of a plethora of mutations. However, these types of gene regulatory studies have been complicated by the lack of suitable cell lines, most of which do not exactly replicate the gene expression patterns observed in vivo. We reasoned that cells established from tissues of YAC transgenic mice might express the transgenes in the correct tissue and developmental stage-specific pattern from which they were derived because YAC transgenic mice display correct regulation of gene expression during ontogeny. We used our human beta-globin locus YAC (beta-YAC) transgenic mice to demonstrate this approach. All existing erythroid cell lines coexpress beta-like globins from different developmental stages or express them inappropriately based on the developmental stage from which they were obtained. Cell populations were established from the adult bone marrow (BM) of beta-YAC transgenic mice, which express exclusively adult beta-globin, using dimerizer technology. A derivative of the thrombopoietin receptor (mpl) was used to bring the proliferative status of primary BM marrow cells under the control of a small molecule drug called a chemical inducer of dimerization (CID). Cells generated in this manner can be expanded to extremely large numbers, remain strictly CID-dependent, and retain megakaryocytic, erythroid, and granulocytic potential. Marrow cells transduced with a retrovirus vector encoding the mpl derivative proliferated extensively in the presence of the CID, AP20187. RNAse protection assays demonstrated that the transcripts for human beta-globin and mouse alpha-globin were present, while gamma-globin transcripts were absent, thus, these cells had the predicted expression phenotype. Exposure to 5-azacytidine or introduction of a hereditary persistence of fetal hemoglobin mutation activated gamma-globin, which was expressed in addition to beta-globin, again consistent with the predicted expression profile of these cells. This approach extends the usefulness of YAC transgenic mice for the generation of cell lines amenable to more detailed studies regarding gene regulation.

Animals↗

PubMed2001

Delineating developmental and metabolic pathways in vivo by expression profiling using the RIKEN set of 18,816 full-length enriched mouse cDNA arrays.

We have systematically characterized gene expression patterns in 49 adult and embryonic mouse tissues by using cDNA microarrays with 18,816 mouse cDNAs. Cluster analysis defined sets of genes that were expressed ubiquitously or in similar groups of tissues such as digestive organs and muscle. Clustering of expression profiles was observed in embryonic brain, postnatal cerebellum, and adult olfactory bulb, reflecting similarities in neurogenesis and remodeling. Finally, clustering genes coding for known enzymes into 78 metabolic pathways revealed a surprising coordination of expression within each pathway among different tissues. On the other hand, a more detailed examination of glycolysis revealed tissue-specific differences in profiles of key regulatory enzymes. Thus, by surveying global gene expression by using microarrays with a large number of elements, we provide insights into the commonality and diversity of pathways responsible for the development and maintenance of the mammalian body plan.

Animals↗

PubMed2003

Evaluation of light regulatory potential of Calvin cycle steps based on large-scale gene expression profiling data.

Although large-scale gene expression data have been studied from many perspectives, they have not been systematically integrated to infer the regulatory potentials of individual genes in specific pathways. Here we report the analysis of expression patterns of genes in the Calvin cycle from 95 Arabidopsis microarray experiments, which revealed a consistent gene regulation pattern in most experiments. This identified pattern, likely due to gene regulation by light rather than feedback regulations of the metabolite fluxes in the Calvin cycle, is remarkably consistent with the rate-limiting roles of the enzymes encoded by these genes reported from both experimental and modeling approaches. Therefore, the regulatory potential of the genes in a pathway may be inferred from their expression patterns. Furthermore, gene expression analysis in the context of a known pathway helps to categorize various biological perturbations that would not be recognized with the prevailing methods.

Arabidopsis↗

PubMed2002

Application of restriction display PCR in preparing the probes of the gene chip for investigating gene expression profile of K562 cells.

OBJECTIVE: To collect the gene fragments of the gene chips for investigating the expression profile of K562 cells. METHODS: The mRNA was extracted from cultured K562 cells to obtain cDNA by reverse transcription-PCR. The gene fragment products of different groups were acquired and isolated by reverse display PCR (RD-PCR). RESULT: The probes for the gene chip were successfully prepared. CONCLUSION: RD-PCR adapted in this study suits the needs for collecting the probes for the gene chips.

DNA Probes↗

PubMed2005

Expression profiling of murine intestinal adenomas reveals early deregulation of multiple matrix metalloproteinase (Mmp) genes.

Initiation of intestinal tumours occurs as a consequence of aberrant Wnt signalling. This causes altered expression of a number of genes which provides the mechanistic basis of neoplastic change in normal epithelium. In order to identify these genes, expression profiles of normal intestinal mucosa and intestinal adenomas from multiple intestinal neoplasia (Min) mice were compared. A total of 116 genes were found to show significant changes in expression in adenomas compared with normal mucosa. Functional classification of these genes clearly identified the biological processes of cellular adhesion and matrix remodelling to be profoundly affected. Notably, three members of the matrix metalloproteinase (Mmp) gene family (Mmp10, Mmp13, and Mmp14) were consistently up-regulated in tumour tissue. To extend these data, expression of 17 Mmp genes was defined using quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR). Several Mmp genes were profoundly up-regulated and every tumour showed overexpression of at least four Mmp genes. These results underscore the probable importance of interactions between the intestinal epithelium and stroma in early tumour development. Furthermore, the inferred role of Mmps at the adenomatous stage of tumourigenesis suggests that this may represent the optimal therapeutic window for the use of Mmp antagonists as anti-cancer agents.

Adenoma↗

PubMed2005

Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals.

Gene expression profiling was performed on biopsies of affected and unaffected psoriatic skin and normal skin from seven Japanese patients to obtain insights into the pathways that control this disease. HUG95A Affymetrix DNA chips that contained oligonucleotide arrays of approximately 12,000 well-characterized human genes were used in the study. The statistical analysis of the Affymetrix data, based on the ranking of the Student t-test statistic, revealed a complex regulation of molecular stress and immune gene responses. The majority of the 266 induced genes in affected and unaffected psoriatic skin were involved with interferon mediation, immunity, cell adhesion, cytoskeleton restructuring, protein trafficking and degradation, RNA regulation and degradation, signalling transduction, apoptosis and atypical epidermal cellular proliferation and differentiation. The disturbances in the normal protein degradation equilibrium of skin were reflected by the significant increase in the gene expression of various protease inhibitors and proteinases, including the induced components of the ATP/ubiquitin-dependent non-lysosomal proteolytic pathway that is involved with peptide processing and presentation to T cells. Some of the up-regulated genes, such as TGM1, IVL, FABP5, CSTA and SPRR, are well-known psoriatic markers involved in atypical epidermal cellular organization and differentiation. In the comparison between the affected and unaffected psoriatic skin, the transcription factor JUNB was found at the top of the statistical rankings for the up-regulated genes in affected skin, suggesting that it has an important but as yet undefined role in psoriasis. Our gene expression data and analysis suggest that psoriasis is a chronic interferon- and T-cell-mediated immune disease of the skin where the imbalance in epidermal cellular structure, growth and differentiation arises from the molecular antiviral stress signals initiating inappropriate immune responses.

Adult↗

PubMed2003

Combined histomorphometric and gene-expression profiling applied to toxicology.

We have developed a unique methodology for the combined analysis of histomorphometric and gene-expression profiles amenable to intensive data mining and multisample comparison for a comprehensive approach to toxicology. This hybrid technology, termed extensible morphometric relational gene-expression analysis (EMeRGE), is applied in a toxicological study of time-varied vehicle- and carbon-tetrachloride (CCl4)-treated rats, and demonstrates correlations between specific genes and tissue structures that can augment interpretation of biological observations and diagnosis.

Animals↗