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PubMed2004

Gene expression profiling of 1p35-36 genes in neuroblastoma.

Deletion of the chromosome 1p36 region is a frequent abnormality in neuroblastoma. To gain further insights into the role of this alteration in oncogenesis, we have constructed a specific cDNA microarray representing most known genes and ESTs from the 1p35-36 region and analysed the expression profiles of 15 neuroblastoma cell lines and 28 neuroblastoma tumours. Hierarchical clustering using expression levels of 320 cDNAs from 1p35-36 separated localized or 4S cases without 1p deletion from advanced stages and cell lines. Supervised learning classification enabled to predict reliably the status of chromosome 1p according to its expression profile. Around 15% of the genes or ESTs presented a significantly decreased expression in samples with 1p deletion as compared to 1p-normal samples suggesting that 1p deletion results in a gene dosage effect on a subset of genes critical for the development of 1p-deleted neuroblastoma. Several genes presumed to have functions in neural differentiation (CDC42, VAMP3, CLSTN1), signal transduction in neural cells (GNB1) and cell cycle regulation (STMN1, RPA2, RBAF600, FBXO6, MAD2L2) exhibited a decreased expression in samples presenting 1p deletion. The identification of such genes provides baseline information for further studies to elucidate how these genes could individually or collectively play a critical role in neuroblastoma tumorigenesis.

Cell Line, Tumor↗

PubMed2006

Gene expression profile in immunologically injured liver cell of mice.

To study the gene expression profiles between immunologically injured liver cell and normal liver cell of mice and to screen on a large scale the differentially expressed genes associated with the formation of liver injury, the experimental mice were randomly divided into the normal group for controlling and the immunologically liver-injured group induced by BCG and LPS. The liver mRNA of the two groups were extracted respectively and reversely-transcribed to cDNA with the incorporation of different fluorescence (Cy3, Cy5) labeled dUTP as the hybridization probes. The mixed probes were hybridized to the cDNA microarray chips. The fluorescent signal results were acquired by scanner ScanArray 4000 and analyzed with software GenePix Pro 3.0. Among the 14112 target genes, 293 genes were found to be significantly differentially expressed, in which 188 genes were up-regulated and 105 genes were down-regulated. Based on the analysis of biological functions of those differentially expressed genes, it was indicated that the occurrence and development of mouse liver damage induced by BCG and LPS were highly correlated with the processes of immune reactions, cell synthesis, metabolism, apoptosis and transportation in liver cell, which might be quite important for elucidating the regulatory network of gene expression associated with the liver damage, also important for finally discovering the pathogenic mechanisms of immunological liver damage.

Alanine Transaminase↗

PubMed2004

Identification of a gene expression profile that differentiates between ischemic and nonischemic cardiomyopathy.

BACKGROUND: Gene expression profiling refines diagnostic and prognostic assessment in oncology but has not yet been applied to myocardial diseases. We hypothesized that gene expression differentiates ischemic and nonischemic cardiomyopathy, demonstrating that gene expression profiling by clinical parameters is feasible in cardiology. METHODS AND RESULTS: Affymetrix U133A microarrays of 48 myocardial samples from Johns Hopkins Hospital (JHH) and the University of Minnesota (UM) obtained (1) at transplantation or left ventricular assist device (LVAD) placement (end-stage; n=25), (2) after LVAD support (post-LVAD; n=16), and (3) from newly diagnosed patients (biopsy; n=7) were analyzed with prediction analysis of microarrays. A training set was used to develop the profile and test sets to validate the accuracy of the profile. An etiology prediction profile developed in end-stage JHH samples was tested in independent samples from both JHH and UM with 100% sensitivity and 100% specificity in end-stage samples and 33% sensitivity and 100% specificity in both post-LVAD and biopsy samples. The overall sensitivity was 89% (95% CI 75% to 100%), and specificity was 89% (95% CI 60% to 100%) over 210 random partitions of end-stage samples into training and test sets. Age, gender, and hemodynamic differences did not affect the profile's accuracy in stratified analyses. Select gene expression was confirmed with quantitative polymerase chain reaction. CONCLUSIONS: Gene expression profiling accurately predicts cardiomyopathy etiology, is generalizable to samples from separate institutions, is specific to disease stage, and is unaffected by differences in clinical characteristics. This strongly supports ongoing efforts to incorporate expression profiling-based biomarkers in determining prognosis and response to therapy in heart failure.

Adult↗

PubMed2006

Difference of gene expression profiles between Barrett's esophagus and cardia intestinal metaplasia by gene chip.

The difference of gene expression profile changes in Barrett's esophagus (BE) and cardia intestinal metaplasia (CIM) epithelium was studied and the novel associated genes were screened in the early stage by cDNA microarray. The cDNA retro-transcribed from equal quantity mRNA from BE and CIM epithelial tissues were labeled with Cy3 and Cy5 fluorescence as probes. The mixed probe was hybridized with three pieces BiostarH-40s double dot human whole gene chip. The chips were scanned with a ScanArray 4000. The acquired images were analyzed using GenePix Pro 3.0 software. It was found a total of 141 genes were screened out that exhibited differentially expression more than 2 times in all three chips. It was identified that in gene expression profiles of BE, 74 genes were up-regulated and 67 down-regulated as compared with CIM. The comparison between the difference of gene expression profile changes in BE and CIM epithelia revealed that there existed the difference between BE and CIM at gene level. 141 genes with the expression more than two time were probably related to the occurrence and development of BE and the promotion or progress in adenocarcinoma.

Barrett Esophagus↗

PubMed2004

Modified serial analysis of gene expression method for construction of gene expression profiles of microbial eukaryotic species.

Serial analysis of gene expression (SAGE) is a powerful approach for the identification of differentially expressed genes, providing comprehensive and quantitative gene expression profiles in the form of short tag sequences. Each tag represents a unique transcript, and the relative frequencies of tags in the SAGE library are equal to the relative proportions of the transcripts they represent. One of the major obstacles in the preparation of SAGE libraries from microorganisms is the requirement for large amounts of starting material (i.e., mRNA). Here, we present a novel approach for the construction of SAGE libraries from small quantities of total RNA by using Y linkers to selectively amplify 3' cDNA fragments. To validate this method, we constructed comprehensive gene expression profiles of the toxic dinoflagellate Pfiesteria shumwayae. SAGE libraries were constructed from an actively toxic fish-fed culture of P. shumwayae and from a recently toxic alga-fed culture. P. shumwayae-specific gene transcripts were identified by comparison of tag sequences in the two libraries. Representative tags with frequencies ranging from 0.026 to 3.3% of the total number of tags in the libraries were chosen for further analysis. Expression of each transcript was confirmed in separate control cultures of toxic P. shumwayae. The modified SAGE method described here produces gene expression profiles that appear to be both comprehensive and quantitative, and it is directly applicable to the study of gene expression in other environmentally relevant microbial species.

Animals↗

PubMed2000

Human protein tyrosine phosphatase-like gene: expression profile, genomic structure, and mutation analysis in families with ARVD.

The mouse protein tyrosine phosphatase-like gene (Ptpla) was recently cloned and data suggested that it plays a role in myogenesis and cardiogenesis. The human homologue (PTPLA) was mapped to chromosome 10p13-14, a region where we have mapped a locus responsible for arrhythmogenic right ventricular dysplasia (ARVD). As a positional candidate gene, we characterized PTPLA by determining its tissue expression, its genomic structure, and we also screened for mutations in the ARVD patients. Northern analysis demonstrated PTPLA is preferentially expressed in both adult and fetal heart. A much lower expression was detected in skeletal and smooth muscle tissues. Virtually no expression was observed in other tissues. The protein-encoding sequences of PTPLA consist of seven exons. A sequence variation (Lys64Gln) was found in all the affecteds in a large ARVD family. However, the same variant was also detected in normal control subjects (three alleles/100 chromosomes). Thus, the variant (Lys64Gln) is not responsible for ARVD in our family and is a benign polymorphism. Nevertheless, its tissue-specific expression in the developing and adult heart suggest PTPLA has a role in regulating cardiac development, differentiation, or other cellular events. The genomic structure and intragenic polymorphism of PTPLA should be useful for further clinical and genetic studies such as gene targeting of PTPLA.

Arrhythmogenic Right Ventricular Dysplasia↗

PubMed2005

Random walk models for bayesian clustering of gene expression profiles.

The analysis of gene expression temporal profiles is a topic of increasing interest in functional genomics. Model-based clustering methods are particularly interesting because they are able to capture the dynamic nature of these data and to identify the optimal number of clusters. We have defined a new Bayesian method that allows us to cope with some important issues that remain unsolved in the currently available approaches: the presence of time dislocations in gene expression, the non-stationarity of the processes generating the data, and the presence of data collected on an irregular temporal grid. Our method, which is based on random walk models, requires only mild a priori assumptions about the nature of the processes generating the data and explicitly models inter-gene variability within each cluster. It has first been validated on simulated datasets and then employed for the analysis of a dataset relative to serum-stimulated fibroblasts. In all cases, the results have been promising, showing that the method can be helpful in functional genomics research.

Journal Article↗

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↗

PubMed2001

Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis.

Human protein C is a natural anticoagulant factor, and a recombinant activated form of the molecule (rhAPC) is completing clinical evaluation for treatment of severe sepsis. Because of the pathophysiologic role of endothelial dysfunction in severe inflammatory disease and sepsis, we explored the possibility that rhAPC might directly modulate endothelial function, independent of its anticoagulant activity. Using broad transcriptional profiling, we show that rhAPC directly modulates patterns of endothelial cell gene expression clustering into anti-inflammatory and cell survival pathways. rhAPC directly suppressed expression of p50 and p52 NFkappaB subunits, resulting in a functional decrease in NFkappaB binding at target sites. Further, rhAPC blocked expression of downstream NFkappaB regulated genes following tumor necrosis factor alpha induction, including dose-dependent suppression of cell adhesion expression and functional binding of intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. Further, rhAPC modulated several genes in the endothelial apoptosis pathway, including the Bcl-2 homologue protein and inhibitor of apoptosis protein. These pathway changes resulted in the ability of rhAPC to inhibit the induction of apoptosis by the potent inducer, staurosporine. This new mechanistic understanding of endothelial regulation and the modulation of tumor necrosis factor-induced endothelial dysfunction creates a novel link between coagulation, inflammation, and cell death and provides insight into the molecular basis for the efficacy of APC in systemic inflammation and sepsis.

Apoptosis↗

PubMed2006

Gene expression profiling and outcome prediction in non-Hodgkin lymphoma.

Gene expression profiling with microarrays has provided new insights into the molecular biology of tumors can that underlie differences in responses to therapy and patient outcomes. In diffuse large B-cell lymphoma, gene expression profiling has revealed at least 2 diseases that are strikingly different in their response to chemotherapy and the inhibition of critical oncogenic pathways. In follicular lymphoma, gene expression profiling showed that the host immune response to tumors is an important determinant of outcome and can strongly predict survival at the time of diagnosis. The application of immunologic therapies that modify the host immune response could have a major effect on survival in patients with follicular lymphoma. Thus, the application of gene expression profiling in non-Hodgkin lymphoma provides important prognostic information at the time of diagnosis and can be translated into therapeutic options that improve patient outcomes.

Disease-Free Survival↗

PubMed2004

Profiles of gene expression in human autoimmune disease.

Human autoimmune diseases arise from complex interactions between genetic and environmental factors, result from immune attack upon target tissues, and affect 3-5% of the population. We compared gene expression profiles (>4000 genes) in the peripheral blood mononuclear cells of normal individuals after immunization to individuals with four different autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus, and multiple sclerosis). All autoimmune individuals, including unaffected first-degree relatives, share a common gene expression profile that is completely distinct from the immune profile. Therefore, this expression pattern is not simply a recapitulation of the immune response to nonself, is not a result of the disease process, and results, as least in part, from genetic factors. Surprisingly, these genes are clustered in chromosomal domains suggesting there is some genome-wide logic to this unique expression pattern. These data argue that that there is a constant pattern of gene expression in autoimmunity that is independent of the specific autoimmune disease and clinical parameters associated with any individual autoimmune disease.

Autoimmune Diseases↗

PubMed2004

Effect of TERT and ATM on gene expression profiles in human fibroblasts.

Telomeres protect chromosomes from degradation, end-to-end fusion, and illegitimate recombination. Loss of telomeres may lead to cell death or senescence or may cause genomic instability, leading to tumor formation. Expression of human telomerase reverse transcriptase (TERT) in human fibroblast cells elongates their telomeres and extends their lifespan. Ataxia telangiectasia mutated (ATM) deficiency in A-T human fibroblasts results in accelerated telomere shortening, abnormal cell-cycle response to DNA damage, and early senescence. Gene expression profiling was performed by serial analysis of gene expression (SAGE) on BJ normal human skin fibroblasts, A-T cells, and BJ and A-T cells transduced with TERT cDNA and expressing telomerase activity. In the four SAGE libraries, 36,921 unique SAGE tags were detected. Pairwise comparisons between the libraries showed differential expression levels of 1%-8% of the tags. Transcripts affected by both TERT and ATM were identified according to expression patterns, making them good candidates for further studies of pathways affected by both TERT and ATM. These include MT2A, P4HB, LGALS1, CFL1, LDHA, S100A10, EIF3S8, RANBP9, and SEC63. These genes are involved in apoptosis or processes related to cell growth, and most have been found to be deregulated in cancer. Our results have provided further insight into the roles of TERT and ATM by identifying genes likely to be involved in their function. Supplementary material for this article can be found on the Genes, Chromosomes and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html.

Ataxia Telangiectasia↗

PubMed2006

Gene expression profile study in CFTR mutated bronchial cell lines.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis conductance transmembrane regulator (CFTR). Symptoms are pancreatic insufficiency, chronic obstructive lung disease, liver disease, chronic sinusitis and infertility in male patients. The phenotypic variability may be explained only in part by the more than 1200 CFTR mutations, which are grouped into six different classes, according to their effect on the protein ranging from a severe (no synthesis or blocked processing) to mild mutation (altered conductance or reduced synthesis). However, it is now accepted that other genes (CF modifiers) influence the phenotypic spectrum of the disease. In order to identify CF modifier genes, we built a low-density home-made oligoarray containing 144 genes selected according to biochemical criteria and evaluated their expression in two CF bronchial epithelial cell lines (CuFi1 F508del/F508del; CuFi3 F508del/R553X). If we consider both cell lines, 38 genes (26.3%) show an altered expression pattern with a threshold > +/-1.5. Of these 38 genes, 12 are altered in CuFi1, and 26 in CuFi3. Some of these genes share the same expression pattern in both cell lines, while others have a different behaviour. These results were validated by a QRT-PCR assay (R2 CuFi1 = 0.81 and R2 CuFi3 = 0.91). These data could suggest that the presence of a class I allele (R553X) determines a more profound alteration of gene expression pattern than the presence of a class II allele (F508del). The identification of the genes altered by a specific CF mutation could lead to the development of a pharmacological approach specific for different CFTR genotypes.

Alleles↗

PubMed1999

Representative cDNA libraries and their utility in gene expression profiling.

An increasing interest in gene expression profiles in human diseases has led to the use of microdissected tumors and biopsies in gene discovery approaches. Since many of these clinical samples yield extremely small amounts of RNA, reproducible methods are needed to amplify this RNA while maintaining the original message profile. Using the SMART cDNA Synthesis Method, we show that high-, medium- and low-abundance transcripts can be amplified in a representative fashion and that the resulting cDNA can also be used as a complex probe to confirm gene expression differences identified by other techniques.

DNA, Complementary↗

PubMed2001

Comparative expressed-sequence-tag analysis of differential gene expression profiles in BmNPV-infected BmN cells.

To compare the gene expression profiles of uninfected and Bombyx mori nucleopolyhedrovirus (BmNPV)-infected BmN cells, we constructed four cDNA libraries for mock-infected cells, and cells at 2, 6, and 12 h postinfection (h.p.i.). A total of 2645 partial sequences obtained for expressed-sequence-tags (ESTs) from the libraries were categorized using BLAST searches of the public database and the BmNPV genome sequence. The following proportions of BmNPV-derived ESTs were observed: 0.4, 4.5, and 57% at 2, 6, and 12 h.p.i, respectively. Moreover, 31 BmNPV open reading frames (ORFs) were newly identified for transcripts and the baculovirus-repeated ORFs (bro) showed the highest levels of expression in the 12 h.p.i. library. Most of the host genes decreased in number as the infection progressed. However, several, including cytochrome c oxidase 1, increased in the late stages of infection. Two apoptosis-related host genes were also identified.

Amino Acid Sequence↗

PubMed2005

Multi-species microarrays reveal the effect of sequence divergence on gene expression profiles.

Interspecies comparisons of gene expression levels will increase our understanding of the evolution of transcriptional mechanisms and help to identify targets of natural selection. This approach holds particular promise for apes, as many human-specific adaptations are thought to result from differences in gene expression rather than in coding sequence. To date, however, all studies directly comparing interspecies gene expression have been performed on single-species arrays, so that it has been impossible to distinguish differential hybridization due to sequence mismatches from underlying expression differences. To evaluate the severity of this potential problem, we constructed a new multiprimate cDNA array using probes from human, chimpanzee, orangutan, and rhesus. We find a large effect of sequence divergence on hybridization signal, even in the closest pair of species, human and chimpanzee. By comparing single-species array analyses with results from multispecies arrays, we examine how estimates of differential gene expression are affected by sequence divergence. Our results indicate that naive use of single-species arrays in direct interspecies comparisons can yield spurious results.

Animals↗

PubMed2004

Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors.

Hairy cell leukemia (HCL) is a chronic B cell malignancy characterized by the diffuse infiltration of bone marrow and spleen by cells displaying a typical "hairy" morphology. However, the nature of the HCL phenotype and its relationship to normal B cells and to other lymphoma subtypes remains unclear. Using gene expression profiling, we show here that HCL displays a homogeneous pattern of gene expression, which is clearly distinct from that of other B cell non-Hodgkin lymphomas. Comparison with the gene expression profiles of purified normal B cell subpopulations, including germinal center (GC), pre-GC (naive), and post-GC (memory) B cells, shows that HCL cells are more related to memory cells, suggesting a derivation from this B cell population. Notably, when compared with memory cells, HCL cells displayed a remarkable conservation in proliferation, apoptosis, and DNA metabolism programs, whereas they appeared significantly altered in the expression of genes controlling cell adhesion and response to chemokines. Finally, these analyses have identified several genes that are specifically expressed in HCL and whose expression was confirmed at the protein level by immunocytochemical analysis of primary HCL cases. These results have biological implications relevant to the pathogenesis of this malignancy as well as clinical implications for its diagnosis and therapy.

B-Lymphocytes↗

PubMed2003

Gene expression profile changes in NB4 cells induced by arsenic trioxide.

AIM: To investigate the gene expression profiles of acute promyelocytic leukemia (APL) cell line NB4 treated with arsenic trioxide (As2O3) using cDNA microarray. METHODS: Two cDNA probes were prepared through reverse transcription from mRNA of NB4 cells treated with or without arsenic trioxide. The probes were labeled with Cy3 and Cy5 fluorescence dyes individually, hybridized with cDNA microarray representing 1003 different human genes, and their fluorescent intensities were scanned. The genes were screened through the analysis of the difference in two gene expression profiles. RESULTS: The analysis of gene expression profiles indicated that after the treatment of arsenic trioxide (0.5 micromol/L) 3 genes were up-regulated, among which, PSMB6 gene was involved in proteasome degradation pathway, and 18 genes related to RNA processing, protein synthesis, and signal transduction were down-regulated. CONCLUSION: PSMB6 and ITGB1 genes may be related to the differentiation and/or apoptosis of NB4 cells induced by As2O3.

Antineoplastic Agents↗