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PubMed2004

ESTs, cDNA microarrays, and gene expression profiling: tools for dissecting plant physiology and development.

Gene expression profiling holds tremendous promise for dissecting the regulatory mechanisms and transcriptional networks that underlie biological processes. Here we provide details of approaches used by others and ourselves for gene expression profiling in plants with emphasis on cDNA microarrays and discussion of both experimental design and downstream analysis. We focus on methods and techniques emphasizing fabrication of cDNA microarrays, fluorescent labeling, cDNA hybridization, experimental design, and data processing. We include specific examples that demonstrate how this technology can be used to further our understanding of plant physiology and development (specifically fruit development and ripening) and for comparative genomics by comparing transcriptome activity in tomato and pepper fruit.

DNA, Complementary↗

PubMed2003

Analyzing tumor gene expression profiles.

A brief introduction to high throughput technologies for measuring and analyzing gene expression is given. Various supervised and unsupervised data mining methods for analyzing the produced high-dimensional data are discussed. The main emphasis is on supervised machine learning methods for classification and prediction of tumor gene expression profiles. Furthermore, methods to rank the genes according to their importance for the classification are explored. The approaches are illustrated by exploratory studies using two examples of retrospective clinical data from routine tests; diagnostic prediction of small round blue cell tumors (SRBCT) of childhood and determining the estrogen receptor (ER) status of sporadic breast cancer. The classification performance is gauged using blind tests. These studies demonstrate the feasibility of machine learning-based molecular cancer classification.

Adult↗

PubMed2003

Gene-expression profiles of human tumor xenografts in nude mice treated orally with the EGFR tyrosine kinase inhibitor ZD1839.

To date, no single or multiple molecular markers have been successful in predicting sensitivity of individual patients to anti-cancer drugs. As the nature of a specific cancer is considered to be defined by the proteins being expressed in the tumor cells, systematic analysis of gene-expression profiles may provide information reflecting sensitivity of a given tumor to certain drugs. Recent progress in genome technology has enabled us to examine expression profiles of thousands of genes in a single experiment. We used this approach to examine 13 xenografts of human tumors implanted into nude mice for sensitivity to an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa). To identify genes that might be associated with sensitivity to this drug we used a cDNA microarray representing 23,040 genes to analyze expression profiles of the 13 xenografts and identified 114 genes whose expression levels correlated significantly with sensitivity of the tumors to ZD1839. We then investigated alteration of expression profiles in response to the ZD1839 treatment in four non-small cell lung cancer (NSCLC) xenografts, of which two (LC6 and LC11) were sensitive and the other two (Lu116 and L27) were resistant to this EGFR-TKI. Systematic analysis of expression at various time points during oral treatment for 14 days, compared with corresponding untreated samples, identified a set of genes whose expression levels changed in the two sensitive tumors but not in the two resistant tumors. The data obtained here should provide useful information on the molecular mechanism underlying clinical responses to EGFR-TKIs, aid the development of novel therapies for lung cancer, and potentially identify predictive molecular markers for sensitivity to ZD1839.

Administration, Oral↗

PubMed2002

Mouse glioma gene expression profiling identifies novel human glioma-associated genes.

Based on previous studies demonstrating increased RAS activity in human astrocytomas, we developed a transgenic mouse model (B8) that targets an activated RAS molecule to astrocytes. Within 3 to 4 months after birth, these mice develop high-grade astrocytomas that are histologically identical to human astrocytomas. To characterize genetic events associated with B8 mouse astrocytoma formation, we employed comparative gene expression profiling of wild-type cultured mouse astrocytes, non-neoplastic B8 astrocytes, B8 astrocytoma cultures, and two other astrocytoma cultures from independently derived RAS transgenic mouse lines. We identified several classes of gene expression changes, including those associated with the non-neoplastic state in the B8 transgenic mouse, those associated with astrocytoma formation, and those specifically associated with only one of the three independently derived transgenic mouse astrocytomas. Differential expression of several unique genes was confirmed at the protein level in both the RAS transgenic mouse astrocytomas and two human glioblastoma multiforme cell lines. Furthermore, reexpression of one of these downregulated astrocytoma-associated proteins, GAP43, resulted in C6 glioma cell growth suppression. The use of this transgenic mouse model to identify novel genetic changes that might underlie the pathogenesis of human high-grade astrocytomas provides a unique opportunity to discover future targets for brain tumor therapy.

Animals↗

PubMed2004

Gene expression profile of the rat eye iridocorneal angle: NEIBank expressed sequence tag analysis.

PURPOSE: To characterize gene expression pattern in the combined tissues of the rat iridocorneal angle by expressed sequence tag (EST) analysis, as part of the NEIBank project. METHODS: RNA was extracted from dissected tissues of the rat iridocorneal angle (iris, ciliary body, trabecular meshwork, and Schlemm's canal) and used to construct unamplified, non-normalized cDNA libraries in the pSPORT1 vector. Approximately 5000 clones were sequenced from the 5'-end. Clones were clustered and identified using the GRIST software, a procedure based on BLAST comparisons. Complete sequences of several novel cDNAs showing eye-preferred expression patterns were obtained. The expression patterns of several genes have been investigated by Northern blot and in situ hybridization, as well as by RT-PCR. RESULTS: After analysis and removal of non-mRNA sequences, 2195 independent clusters, potentially representing individual eye angle-expressed clones were obtained. The expression profile of the combined rat eye angle tissues was more similar to that of the human iris than to human trabecular meshwork. Several cDNAs encoding transcription factors essential for normal eye development and function including Pax-6, Six3, c-Maf, Maf1, Sox-4, Foxc1, Rx, and Ldb2 were present among sequenced clones. A number of tested cDNAs showed eye-preferred expression patterns. Myocilin, which is abundant in human eye angle tissues, was not observed in the rat collection; however, transcripts for three other olfactomedin-domain proteins were seen. Latrotoxin receptor (CL1AA) and optimedin were shown to be expressed in the iris and ciliary body, as well as in the ganglion and inner nuclear cell layers of the retina, whereas the rat orthologue of the human HNOEL-iso gene was expressed in the iris and sclera and less actively in the trabecular meshwork, retina, and optic nerve. CONCLUSIONS: The iridocorneal libraries are a good source of novel uncharacterized genes and molecular markers for the tissues of the eye angle. Although myocilin is not abundantly expressed in rat eye angle, other olfactomedin-containing genes are expressed there and may play important roles in normal eye function and disease.

Amino Acid Sequence↗

PubMed2004

[Gene expression profile in early differentiation of K562 cells induced by matrine].

OBJECTIVE: To compare gene expression profile in K562 cells induced by matrine, so as to screen for differentiation related genes. METHODS: K562 cells were exposed to 0.1 mg/ml matrine for 3 hours, and gene expression profiles in matrine-treated and non-treated cells were studied by cDNA microarray. RESULTS: From 8465 screened genes, 30 differentially expressed genes were found. Among them 18 showed decreased expression including oncogene and proto-oncogene, signal transduction gene, DNA binding and transcription gene etc, 12 showed increased expression including cell receptor gene, immune-associated gene, metabolism-associated gene etc in matrine-treated K562 cells as compared with that in non-treated cell. CONCLUSION: The genes, that are closely associated with differentiation of can-cer cell, could be the potential targets for cancer treatment.

Alkaloids↗

PubMed2001

Gene expression profiles in Ciona intestinalis tailbud embryos.

A set of 3423 expressed sequence tags derived from the Ciona intestinalis tailbud embryos was categorized into 1213 independent clusters. When compared with DNA Data Bank of Japan database, 502 clusters of them showed significant matches to reported proteins with distinct function, whereas 184 lacked sufficient information to be categorized (including reported proteins with undefined function) and 527 had no significant similarities to known proteins. Sequence similarity analyses of the 502 clusters in relation to the biosynthetic function, as well as the structure of the message population at this stage, demonstrated that 390 of them were associated with functions that many kinds of cells use, 85 with cell-cell communication and 27 with transcription factors and other gene regulatory proteins. All of the 1213 clusters were subjected to whole-mount in situ hybridization to analyze the gene expression profiles at this stage. A total of 387 clusters showed expression specific to a certain tissue or organ; 149 showed epidermis-specific expression; 34 were specific to the nervous system; 29 to endoderm; 112 to mesenchyme; 32 to notochord; and 31 to muscle. Many genes were also specifically expressed in multiple tissues. The study also highlighted characteristic gene expression profiles dependent on the tissues. In addition, several genes showed intriguing expression patterns that have not been reported previously; for example, four genes were expressed specifically in the nerve cord cells and one gene was expressed only in the posterior part of muscle cells. This study provides molecular markers for each of the tissues and/or organs that constitutes the Ciona tailbud embryo. The sequence information will also be used for further genome scientific approach to explore molecular mechanisms involved in the formation of one of the most primitive chordate body plans.

Animals↗

PubMed2004

Independent downstream gene expression profiles in the presence of estrogen receptor alpha or beta.

The two known forms of estrogen receptor (ER), alpha and beta, exhibit differences in structure, affinity for certain ligands, and tissue distribution, suggesting differential roles. It is of interest from several perspectives to determine whether the two receptors elicit similar or differing responses within the same cell type in the presence of the same ligand. To evaluate roles of ER, we have examined responses to estrogen in a rat embryonic fibroblast cell line model, normally naive to ER, engineered to stably express ERalpha or ERbeta. Rat1+ERalpha, Rat1+ERbeta, and precursor Rat1 cell lines were treated with estradiol-17beta (E(2); 1 nM) or an ethanol vehicle for 24 h. Total RNA was extracted, and cDNA generated and subjected to suppression subtractive hybridization (SSH), followed by differential screening using dot blot hybridization. In the presence of ERalpha, products were identified that represent classic responses to E(2), including markers for cell proliferation. In the presence of ERbeta, an alternate transcription profile was observed, including upregulation of pro-alpha-2(I) collagen. These data support a model in which ERalpha and ERbeta regulate unique subsets of downstream genes within a given cell type.

Animals↗

PubMed2003

Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR.

The BCR/ABL tyrosine kinase inhibitor, imatinib, has shown substantial effects in blast crises of chronic myelogenous leukemia. However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem for patients being treated with imatinib. In this study, we generated a new imatinib-resistant BCR/ABL-positive cell line, KCL22/SR. The 50% inhibitory concentration of imatinib was 11-fold higher in KCL22/SR than in the imatinib-sensitive parental cell line, KCL22. However, KCL22/SR showed no mutations in the BCR/ABL gene and no increase in the levels of BCR/ABL protein and P-glycoprotein. Furthermore, the level of phosphorylated BCR/ABL protein was suppressed by imatinib treatment, suggesting that mechanisms independent of BCR/ABL signaling are involved in the imatinib resistance in KCL22/SR cells. DNA microarray analyses demonstrated that the signal transduction-related molecules, RAS p21 protein activator and RhoA, which could affect Ras signaling, and a surface tumor antigen, L6, were upregulated, while c-Myb and activin A receptor were downregulated in KCL22/SR cells. Furthermore, imatinib treatment significantly suppressed the level of phosphorylated p44/42 in KCL22 cells but not in KCL22/SR cells, even when BCR/ABL was inhibited by imatinib. These results suggest that various mechanisms, including disturbance of Ras-mitogen-activated protein kinase signaling, are involved in imatinib resistance.

Antineoplastic Agents↗

PubMed2003

Genome-wide cDNA microarray analysis of gene-expression profiles involved in ovarian endometriosis.

Using a cDNA microarray consisting of 23,040 genes, we analyzed gene-expression profiles of ovarian endometrial cysts from 23 patients in order to identify genes involved in endometriosis. By comparing expression patterns between endometriotic tissues and corresponding eutopic endometria, we identified 15 genes that were commonly up-regulated in the endometrial cysts during both proliferative and secretory phases of the menstrual cycle, 42 that were up-regulated only in the proliferative phase, and 40 that were up-regulated only in the secretory phase. The up-regulated elements included genes encoding some HLA antigens, complement factors, ribosomal proteins, and TGFBI. On the other hand, 337 genes were commonly down-regulated throughout the menstrual cycle, 144 only in the proliferative phase, and 835 only in the secretory phase. The down-regulated elements included the tumor suppressor TP53, genes related to apoptosis such as GADD34, GADD45A, GADD45B and PIG11, and the gene encoding OVGP1, a protein involved in maintenance of early pregnancy. Semi-quantitative RT-PCR experiments supported the results of our microarray analysis. These data should provide useful information for finding candidate genes whose products might serve as molecular targets for diagnosis or treatment of endometriosis.

Adult↗

PubMed2004

[Molecular classification in leukemias using gene expression profiling].

A comprehensive approach to the diagnosis in leukemias relies on cytomorphology, cytochemistry, cytogenetics, fluorescence in situ hybridization, multiparameter flow cytometry, and molecular methods. Recently, gene expression profiling using microarrays was invented to measure the expression of thousands of genes in one step. A specific signature stands for the molecular fingerprint of a tumor sample. Therefore, gene expression profiling may lead to a better molecular classification of leukemias and insights into pathophysiology. Furthermore, gene expression profiling may lead to new targeted therapies and can detect genes to be used for minimal residual disease studies. Very recent studies point also to the possibility to use gene expression profiling for prognostication. In conclusion, microarrays may lead to a single platform approach in leukemia diagnosis with quick and very robust results. This new technique should be further validated in parallel to the standard work-flow and has to be proven before substituting other methods in the future.

Algorithms↗

PubMed2002

Soluble interleukin-6 receptor enhanced by oncostatin M induces major changes in gene expression profile of human hepatoma cells.

Interleukin-6 (IL-6) binds to a receptor complex consisting of an 80 kDa binding unit (IL-6R) and gp130 responsible for signal transduction. Due to alternative splicing and/or proteolytic digestion IL-6R occurs in soluble form (sIL-6R), as well. Soluble IL-6R is able to bind to gp130 expressing on nucleated cells, thus sIL-6R makes most cells responsive to IL-6. In this study we found that oncostatin M (OSM), an other gp130 dependent cytokine with proliferation inhibitory potential, increases the expression of both membrane-bound IL-6R and sIL-6R generated by alternative splicing in hepatic and mammary carcinoma cell lines. Furthermore, we studied the functional relevance of the presence and binding of soluble IL-6R to HepG2 cells. Using a cDNA expression array, mRNA levels of about 580 human genes were tested by differential display analysis. Our findings suggest, that elevation of surface density of IL-6R by attachment of sIL-6R induces major modulation in gene expression profile of the hepatoma cells. Soluble IL-6R alone has minor effect, it rather decreases expression of some genes, while incubation with IL-6 and sIL-6R together induces major changes in the mRNA pattern of HepG2 cells. These data strongly suggest that presence and binding of soluble cytokine receptors are important elements of inter-cytokine cross talk and affects actual gene expression profile of responding cells.

Alternative Splicing↗

PubMed2003

Identification of specific gene expression profiles in human mast cells mediated by Toll-like receptor 4 and FcepsilonRI.

Rodent mast cells (MCs) are reported to play a pivotal role in both innate and adaptive immunity. However, there is so far no evidence that human MCs are involved in innate immunity. We found that a functional Toll-like receptor 4 (TLR4) was expressed on human MCs when it was up-regulated by interferon gamma (IFN-gamma). To systematically explore how human MCs modulate the immune system following TLR4-mediated activation and FcepsilonRI aggregation, we used high-density oligonucleotide probe arrays (GeneChip) to compare the lipopolysaccharide (LPS)-induced gene expression profile with the IgE/anti-IgE-mediated profile in MCs. Both a shared core response, and LPS- or anti-IgE-specific programs of gene expression were observed in MCs. Furthermore, MCs exhibited an antiviral response gene program in response to IFN-gamma, and LPS sustained that expression. Compared with the LPS-stimulated gene expression profile of human peripheral blood mononuclear cells, LPS-stimulated MCs specifically induced a subset of genes that included a Th2 cytokine and chemokines that recruit Th2 cells and eosinophils. These results reveal that human MCs express tailored pathogen- and antigen-specific immune responses and that human MCs may play important roles in innate and adaptive immunity.

Chemokine CCL1↗

PubMed2004

Orthologous gene-expression profiling in multi-species models: search for candidate genes.

Microarray-driven gene-expression profiles are generally produced and analyzed for a single specific experimental model. We have assessed an analytical approach that simultaneously evaluates multi-species experimental models within a particular biological condition using orthologous genes as linkers for the various Affymetrix microarray platforms on multi-species models of ventilator-associated lung injury. The results suggest that this approach may be a useful tool in the evaluation of biological processes of interest and selection of process-related candidate genes.

Animals↗

PubMed2002

DNA microarray analysis reveals novel gene expression profiles in collagen-induced arthritis.

Global gene expression was analyzed in early and late collagen-induced arthritis (CIA). Of 8734 cDNAs analyzed, 330 were induced and 55 downregulated greater than twofold in early or late disease. Hierarchical clustering of these 385 cDNAs demonstrated five distinct expression patterns differentiating early from late disease and correlating with histopathologic changes in the paw. Of the 385 cDNAs, 185 are known, characterized genes, the majority of which are not described as playing a role in arthritis. However, several of these genes are involved in pathological processes relating to arthritis, including apoptosis, inflammation, and cellular proliferation. One interesting gene, follistatin-like gene, is highly expressed along the margin of contact between inflammatory synovial pannus and eroding bone, suggesting a role in joint destruction. These results demonstrate that global gene expression profiles distinguish early and late CIA and reveal several genes novel to arthritis the further characterization of which will advance our understanding of arthritis.

Animals↗

PubMed2002

Bayesian infinite mixture model based clustering of gene expression profiles.

MOTIVATION: The biologic significance of results obtained through cluster analyses of gene expression data generated in microarray experiments have been demonstrated in many studies. In this article we focus on the development of a clustering procedure based on the concept of Bayesian model-averaging and a precise statistical model of expression data. RESULTS: We developed a clustering procedure based on the Bayesian infinite mixture model and applied it to clustering gene expression profiles. Clusters of genes with similar expression patterns are identified from the posterior distribution of clusterings defined implicitly by the stochastic data-generation model. The posterior distribution of clusterings is estimated by a Gibbs sampler. We summarized the posterior distribution of clusterings by calculating posterior pairwise probabilities of co-expression and used the complete linkage principle to create clusters. This approach has several advantages over usual clustering procedures. The analysis allows for incorporation of a reasonable probabilistic model for generating data. The method does not require specifying the number of clusters and resulting optimal clustering is obtained by averaging over models with all possible numbers of clusters. Expression profiles that are not similar to any other profile are automatically detected, the method incorporates experimental replicates, and it can be extended to accommodate missing data. This approach represents a qualitative shift in the model-based cluster analysis of expression data because it allows for incorporation of uncertainties involved in the model selection in the final assessment of confidence in similarities of expression profiles. We also demonstrated the importance of incorporating the information on experimental variability into the clustering model. AVAILABILITY: The MS Windows(TM) based program implementing the Gibbs sampler and supplemental material is available at http://homepages.uc.edu/~medvedm/BioinformaticsSupplement.htm CONTACT: medvedm@email.uc.edu

Bayes Theorem↗

PubMed2001

Gene expression profiling of the response to thermal injury in human cells.

The genetic response of human cells to sublethal thermal injury was assessed by gene expression profiling, using macroarrays containing 588 complementary known genes. At 1, 4, 8, and 24 h following thermal injury, RNA was isolated, and a cDNA copy was generated incorporating (33)P and hybridized to Atlas arrays. About one-fifth of the genes on the membrane exhibited a significant elevation or depression in expression (>/=2-fold) by 4 h posttreatment. Genes for heat shock proteins (HSPs) were upregulated as well as genes for transcription factors, growth regulation, and DNA repair. Cluster analysis was performed to assess temporal relationships between expression of genes. Translation of mRNA for some expressed genes, including HSP70 and HSP40, was corroborated by Western blotting. Gene expression profiling can be used to determine information about gene responses to thermal injury by retinal pigment epithelium cells following sublethal injury. The induction of gene expression following thermal injury involves a number of genes not previously identified as related to the stress response.

Blotting, Western↗

PubMed2003

Quick gene expression profiling of promyelocytic cell line HL-60.

OBJECTIVE: A number of techniques have been developed to perform gene expression profiling. We report preliminary results from our exploratory study, using sequential analysis of gene expression (SAGE) technique, to profile the undifferentiated and differentiated HL-60 cells in line with our interest to characterize the cancer phenotype. The aim of the study is to evaluate the technique and to understand the molecular bases of these 2 states of cells. METHODS: HL-60 cells were differentiated after treatment with dimethyl sulfoxide. Tag libraries were prepared from the messenger RNAs of the undifferentiated and differentiated cells according to the SAGE protocol. The search for genes corresponding to the tags was carried out using SAGE software. The tags and the genes from the 2 libraries were compared for their levels of expression. The study was carried out at the King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia during the year 2001. RESULTS: A comparison of tags from the 2 libraries revealed that 151 tags corresponding to 57 genes expressed differentially: 60 tags were elevated and 59 were repressed in the undifferentiated cells. Thirty-two tags were equally expressed in both types of cells. Of the corresponding genes, 25 were expressed at higher, 17 at lower, while 15 were expressed at comparable levels in both cell types. In the profile of undifferentiated cells, the genes involved in mitochondrial function and protein synthesis were prominent, while in the differentiated cells, the genes coding for proteins associated with cell membranes, signal transduction and for cell specific functions were prominent. The genes, expressed equally in both the cell types, were concerned with the maintenance of the living state. CONCLUSION: Sequential analysis of gene expression is a useful technique for gene expression profiling. As previously indicated by others, a dedicated team can generate useful data within reasonable time limits.

Cell Differentiation↗