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PubMed2005

Pathway and ontology analysis: emerging approaches connecting transcriptome data and clinical endpoints.

The increasing use of gene expression profiling offers great promise in clinical research into disease biology and its treatment. Along with the ability to measure changing expression levels in thousands of genes at once, comes the challenge of analyzing and interpreting the vast sets of data generated. Analysis tools are evolving rapidly to meet such challenges. The next step is to interpret observed changes in terms of the biological properties or relationships underlying them. One powerful approach is to make associations between the genes that are under investigation and well-known biochemical or signaling pathways, and further to assess the significance of such associations. Similarly, genes can be mapped to standardized biological categories via an ontology resource. We discuss these approaches and several web-based resources and tools designed to facilitate such analyses. This information can be used to facilitate understanding and to help design more focused experiments for validating the relevance and importance of these biological pathways and processes in human disease and therapeutics.

Animals↗
PubMed2026

Genus-Wide Pan-Genome Analysis of Populus bZIP Transcription Factors with Reanalysis of Public Salt-Stress Transcriptomes.

Basic leucine zipper (bZIP) transcription factors regulate plant development and stress responses, but their genus-wide diversity in Populus remains unclear. We analyzed 19 Populus genomes and retained 1764 bZIP proteins, including 21 independent new loci and four annotation corrections. Of these, 1762 were assigned to 79 orthologous gene groups (OGGs), comprising 43 core, 20 soft-core, 15 shell and one cloud OGG, of which 59 showed copy-number variation. Phylogenetic analysis assigned 74 representative pangenes to 13 subfamilies, with five remaining unclassified and motif patterns differing among subfamilies. Whole-genome duplication (WGD)/segmental duplication accounted for 81.0% of OGG-assigned proteins and contributed predominantly to the conserved component. Although 72.2% of bZIP proteins overlapped a transposable element within the gene body or 2-kb flanks, this proportion was modestly lower than in matched non-bZIP genes, and copy-number-variable OGGs showed no greater TE coverage than invariant OGGs. Among retained homologous comparisons, 97.6% had Ka/Ks ≤ 1, supporting predominant purifying selection. Across the heterogeneous public salt-stress RNA-seq datasets analyzed, no OGG showed a significant, directionally concordant response in at least two Populus taxa. These results reveal a conserved bZIP framework shaped mainly by ancient duplication alongside variable genomic contexts and transcriptional responses.

Populus↗
PubMed2003

Transcriptomic classification of antitumor agents: application to the analysis of the antitumoral effect of SR31747A.

SR31747A is a sigma ligand that exhibits a potent antitumoral activity on various human tumor cell lines both in vitro and in vivo. To understand its mode of action, we used DNA microarray technology combined with a new bioinformatic approach to identify genes that are modulated by SR31747A in different human breast or prostate cancer cell lines. The SR31747A transcriptional signature was also compared with that of seven different representative anticancer drugs commonly used in the clinic. To this aim, we performed a two-dimensional hierarchical clustering analysis of drugs and genes which showed that 1) standard molecules with similar mechanism of action clustered together and 2) SR31747A does not belong to any previously characterized class of standard anticancer drugs. Moreover, we showed that 3) SR31747A mainly exerted its antiproliferative effect by inhibiting the expression of genes playing a key role in DNA replication and cell cycle progression. Finally, contrasting with other drugs, we obtained evidence that 4) SR31747A strongly inhibited the expression of three key enzymes of the nucleotide synthesis pathway (i.e., dihydrofolate reductase, thymidylate synthase, and thymidine kinase) with the latter shown both at the mRNA and protein levels. These results, obtained through a novel molecular approach to characterize and compare anticancer agents, showed that SR31747A exhibits an original mechanism of action, very likely through unexpected targets whose modulations may account for its antitumoral effect.

Antineoplastic Agents↗
PubMed2005

Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes.

Affinity maturation and Ab class switches occur in lymphoid germinal centers (GCs), in which differentiation and maintenance depend on lymphotoxin (LT) signaling and include differentiation of follicular dendritic cells (FDCs). The events leading to FDC and GC maturation are poorly defined. Using several approaches of functional genomics, we enumerated transcripts affected in mice by suppressing LT beta receptor (LTbetaR) signaling and/or overrepresented in FDC-enriched GC isolates. Protein expression analysis of 3 of 12 genes both enriched in FDCs and down-regulated by LTbetaR signaling suppression validated them as FDC markers. Functional analysis of one of these three, clusterin, suggests a role as an FDC-derived trophic factor for GC B cells. Hence, the set of genes presented in this study includes markers emanating from LTbetaR signaling and transcripts relevant to GC and FDC function.

Animals↗
PubMed2001

Transcriptome analysis and crop improvement (a review).

The identification and characterization of differential gene expression from tissues subjected to stress has gained much attention in plant research. The recognition of elements involved in the response to a particular stress enhances the possibility of promoting crop improvement through direct genetic modification. However, the performance of some of the 'first generation' of transgenic plants with the incorporation of a single gene has not always been as expected. These results have stimulated the development of new transgenic constructions introducing more than one gene and capable of modifying complex pathways. Several techniques are available to conduct the analysis of gene regulation, with such information providing the basis for novel constructs specifically designed to modify metabolism. This review deals with techniques that allow the identification and characterization of differentially-expressed genes and the use of molecular pathway information to produce transgenic plants.

DNA Fingerprinting↗
PubMed2002

Monitoring the chromosome 2 intraerythrocytic transcriptome of Plasmodium falciparum using oligonucleotide arrays.

To test the feasibility of using short oligonucleotide probes to monitor transcript levels in Plasmodium falciparum, a microarray was manufactured containing 4,167 (25 base single-stranded) probes derived from the predicted coding region of P. falciparum chromosome 2. RNA samples from three asexual stages (rings, trophozoites, and schizonts) were labeled and hybridized to the arrays. These results were reproducible, and transcripts were detected for 69% of the 210 genes on chromosome 2. In addition, of the 145 expressed genes, 1/3 appeared to be differentially transcribed during the asexual cycle. Some regions of the chromosome appeared to be transcriptionally silent. Results were confirmed by Northern blot analysis and by quantitative reverse transcriptase-polymerase chain reaction. These data validate the use of relatively short 25-mers for monitoring the expression of a genome that is 82% AT rich.

Animals↗
PubMed2002

Extensive oligonucleotide microarray transcriptome analysis of the rat cerebral artery and arachnoid tissue.

Cerebral vessels have certain distinct anatomical and developmental characteristics which are well known, but their characteristic genetic expression profile remains as yet only poorly understood. We investigated gene expression in the rat cerebral artery in comparison with the rat descending aorta, two locations which have obviously different anatomical and developmental characteristics. Since the contamination of cerebral small arteries by arachnoid tissue is to a certain extent inevitable, we also performed a gene expression analysis of arachnoid tissue as a background. In an effort to obtain the necessary quality and quantity of total RNA, a novel freeze-fracture apparatus minimizing the time required for the entire procedure from tissue separation to RNA preparation was used. With the material obtained, a group of genes highly expressed in each tissue was detected by oligonucleotide microarray analysis. In the circle of Willis, peptide-19 (PEP-19), connexin-37 (CXN-37), growth arrest-and DNA damage-inducible gene (GADD45), and the putative G protein coupled receptor RA1c, Notch-1, and jagged-1 were predominantly expressed. In arachnoid tissue, bone morphologic protein (BMP)-7, BMP-6, beta defensin-1, neuroendocrine protein 7B2, thiol-specific antioxidant protein, IL-18, beta-chain clathrin-associated protein complex AP-1, and angiopoietin-2 were highly expressed. In the aorta, most of the abundantly expressed genes related to lipid metabolism. By means of oligonucleotide microarray analysis, the distinct gene expression profiles in the circle of Willis arachnoid tissue, and aorta were made evident. From these findings it is reasonable to conclude that a functional interaction exists between the circle of Willis and arachnoid tissue.

Animals↗
PubMed2026

Transcriptomic shift in ethanol and amino acid metabolic genes regulated by Med15 during alcoholic fermentation.

Organisms that thrive in extreme environments provide natural experiments in evolution, revealing the genetic regulators that orchestrate complex phenotypic change. Wine yeast are specialized strains that are adapted to survive in the wine making environment while producing high concentrations of ethanol. In addition to large genomic changes that differentiate wine yeast from yeast used in other industries, single nucleotide and polyglutamine tract polymorphisms in the transcriptional regulator Med15 are associated with the fermentation efficiency and stress response phenotypes of wine yeast. In this study we investigated the transcriptional differences during wine fermentation in transgenic lab strain yeast having integrated wine yeast MED15 alleles. Compared to the unmodified lab strain (LAB or MED15 LAB ), the same strain in which the MED15 locus was replaced with a MED15 allele from yeast isolated from palm wine, the fermented sap of palm (oil, date, coconut) trees, (WY23, or MED15 WY23 ) exhibited enhanced expression of glycolytic, fermentation, and amino acid biosynthesis genes. Our experimental data confirms the importance of arginine biosynthetic genes during the fermentation process and suggests that the improvement in fermentation efficiency in strains with MED15 alleles from some wine yeast strains may be related to the role of Med15 in expression of the genes of the arginine biosynthetic pathway. The global benefit conferred by polymorphisms in a single transcriptional regulator, makes Med15 a prime target for engineering of strains devoted to various types of alcohol production.

Journal Article↗
PubMed1999

The Genexpress IMAGE knowledge base of the human brain transcriptome: a prototype integrated resource for functional and computational genomics.

Expression profiles of 5058 human gene transcripts represented by an array of 7451 clones from the first IMAGE Consortium cDNA library from infant brain have been collected by semiquantitative hybridization of the array with complex probes derived by reverse transcription of mRNA from brain and five other human tissues. Twenty-one percent of the clones corresponded to transcripts that could be classified in general categories of low, moderate, or high abundance. These expression profiles were integrated with cDNA clone and sequence clustering and gene mapping information from an upgraded version of the Genexpress Index. For seven gene transcripts found to be transcribed preferentially or specifically in brain, the expression profiles were confirmed by Northern blot analyses of mRNA from eight adult and four fetal tissues, and 15 distinct regions of brain. In four instances, further documentation of the sites of expression was obtained by in situ hybridization of rat-brain tissue sections. A systematic effort was undertaken to further integrate available cytogenetic, genetic, physical, and genic map informations through radiation-hybrid mapping to provide a unique validated map location for each of these genes in relation to the disease map. The resulting Genexpress IMAGE Knowledge Base is illustrated by five examples presented in the printed article with additional data available on a dedicated Web site at the address http://idefix.upr420.vjf.cnrs.fr/EXPR++ +/ welcome.html.

Brain Chemistry↗
PubMed1999

The genexpress IMAGE knowledge base of the human muscle transcriptome: a resource of structural, functional, and positional candidate genes for muscle physiology and pathologies.

Sequence, gene mapping, and expression data corresponding to 910 genes transcribed in human skeletal muscle have been integrated to form the muscle module of the Genexpress IMAGE Knowledge Base. Based on cDNA array hybridization, a set of 14 transcripts preferentially or specifically expressed in muscle have been selected and characterized in more detail: Their pattern of expression was confirmed by Northern blot analysis; their structure was further characterized by full-insert cDNA sequencing and cDNA extension; the map location of the corresponding genes was refined by radiation hybrid mapping. Five of the 14 selected genes appear as interesting positional and functional candidate genes to study in relation with muscle physiology and/or specific orphan muscular pathologies. One example is discussed in more detail. The expression profiling data and the associated Genexpress Index2 entries for the 910 genes and the detailed characterization of the 14 selected transcripts are available from a dedicated Web server at. The database has been organized to provide the users with a working space where they can find curated, annotated, integrated data for their genes of interest. Different navigation routes to exploit the resource are discussed.

Base Sequence↗
PubMed2001

[Transcriptome analysis in cancerology: bioinformatics aspects].

Recent technological advances (e.g. various DNA arrays and chips) allow the measurement of expression level (mRNA abundance) for thousand of genes simultaneously, over multiple conditions or time. Initially developed and tested on model systems such as yeast or in vitro cell line cultures, these techniques have recently begun to be applied to the analysis of human cancers. Initial results are promising, and large-scale gene expression profiling is now expected to become a clinical tool for better tumour identification, prognosis, and optimal treatment design. It is thus important that clinicians become familiar with the theoretical principles underlying the interpretation of gene expression profiles as used in three different contexts: gene discovery, tumour class prediction, and molecular diagnosis. This is the purpose of the present article.

Forecasting↗
PubMed2001

[Molecular typing of breast cancer: transcriptomics and DNA microarrays].

Breast cancer is the most frequent and deadly cancer of women. Its great heterogeneity makes prognosis and response to current treatments highly variable and difficult to predict. Mammary oncogenesis remains poorly understood. These issues should benefit from recent development of techniques capable of large-scale molecular analyses. The use of cDNA array techniques allows for the simultaneous analysis of the mRNA expression levels of thousands of genes in mammary tumor cell lines and breast tumors. Expression profiles will help classify tumors and provide new prognostic tools and potential therapeutic targets. They will also boost our knowledge of the molecular events responsible for the development and progression of this cancer.

Breast Neoplasms↗
PubMed2003

Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis.

HER2 (erbB2/neu) is a member of the erbB family of receptor tyrosine kinases and is involved in regulating the growth of several types of human carcinomas. HER2 represents a successful therapeutic target of the biotechnology era as exemplified by the drug Herceptin (trastuzumab), which has clinical activity in a subset of breast cancer patients. Using DNA microarrays, we identified a cohort of genes that are differentially regulated by HER2 in breast epithelial cells. One of the HER2-regulated genes discovered was fatty acid synthase (FAS), which has been shown to be overexpressed in breast cancer as well as other cancers. FAS is implicated in tumorigenesis through its role in cell proliferation and membrane lipid incorporation of neoplastic cells. Here, we demonstrate that HER2-mediated induction of FAS is inhibitable by Herceptin and tyrosine kinase inhibitors of HER2. Through a phosphatidylinositol 3'-kinase-dependent pathway, HER2 stimulates the FAS promoter and ultimately mediates increased fatty acid synthesis. Interestingly, pharmacological inhibition of FAS preferentially induced apoptosis of HER2-overexpressing breast epithelial cells relative to matched vector control cells. These studies characterize a molecular connection between two genes individually implicated in tumorigenesis but never linked together.

Antibodies, Monoclonal↗
PubMed2003

Relevance network between chemosensitivity and transcriptome in human hepatoma cells.

Generally, hepatoma is not a chemosensitive tumor, and the mechanism of resistance to anticancer drugs is not fully elucidated. We aimed to comprehensively evaluate the relationship between chemosensitivity and gene expression profile in human hepatoma cells, by using microarray analysis, and analyze the data by constructing relevance networks. In eight hepatoma cell lines (HLE, HLF, Huh7, Hep3B, PLC/PRF/5, SK-Hep1, Huh6, and HepG2), the baseline expression levels of 2300 genes were measured by cDNA microarray. The concentrations of eight anticancer drugs (nimustine, mitomycin C, cisplatin, carboplatin, doxorubicin, epirubicin, mitoxantrone, and 5-fluorouracil) needed for 50% growth inhibition were examined and used as a measure of chemosensitivity. These data were combined and comprehensive pair-wise correlations between gene expression levels and the 50% growth inhibition values were calculated. Significant correlations with significance were used to construct networks of similarity. Fifty-two relations, including 42 genes, were selected. Among them, nearly 20% were various types of transporters, and most of them negatively correlated with chemosensitivity. Transporter associated with antigen processing 1 was associated with resistance to mitoxantrone, consistent with previous reports. Other transporters were not reported previously to associate with chemosensitivity. Resistance to doxorubicin and its analogue, epirubicin, were positively correlated with topoisomerase II beta expression, whereas it negatively correlated with expression of carboxypeptidases A3 and Z. Response to nimustine was associated with expression of superoxide dismutase 2. Relevance networks identified several negative correlations between gene expression and resistance, which were missed by hierarchical clustering. Our results suggested the necessity of systematically evaluating the transporting systems that may play a major role in resistance in hepatoma. This may provide useful information to modify anticancer drug action in hepatoma.

Antineoplastic Agents↗