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At least 1,549 records · Page 86Linked to original sources
PubMed2003

Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells.

This report describes an unbiased method for systematically determining gene function in mammalian cells. A total of 20,704 predicted human full-length cDNAs were tested for induction of the IL-8 promoter. A number of genes, including those for cytokines, receptors, adapters, kinases, and transcription factors, were identified that induced the IL-8 promoter through known regulatory sites. Proteins that acted through a cooperative interaction between an AP-1 and an unrecognized cAMP response element (CRE)-like site were also identified. A protein, termed transducer of regulated cAMP response element-binding protein (CREB) (TORC1), was identified that activated expression through the variant CRE and consensus CRE sites. TORC1 potently induced known CREB1 target genes, bound CREB1, and activated expression through a potent transcription activation domain. A functional Drosophila TORC gene was also identified. Thus, TORCs represent a family of highly conserved CREB coactivators that may control the potency and specificity of CRE-mediated responses.

Amino Acid Sequence↗
PubMed2005

Genome-wide estimation of gender differences in the gene expression of human livers: statistical design and analysis.

BACKGROUND: Gender differences in gene expression were estimated in liver samples from 9 males and 9 females. The study tested 31,110 genes for a gender difference using a design that adjusted for sources of variation associated with cDNA arrays, normalization, hybridizations and processing conditions. RESULTS: The genes were split into 2,800 that were clearly expressed (expressed genes) and 28,310 that had expression levels in the background range (not expressed genes). The distribution of p-values from the 'not expressed' group was consistent with no gender differences. The distribution of p-values from the 'expressed' group suggested that 8% of these genes differed by gender, but the estimated fold-changes (expression in males/expression in females) were small. The largest observed fold-change was 1.55. The 95% confidence bounds on the estimated fold-changes were less than 1.4 fold for 79.3%, and few (1.1%) exceed 2-fold. CONCLUSION: Observed gender differences in gene expression were small. When selecting genes with gender differences based upon their p-values, false discovery rates exceed 80% for any set of genes, essentially making it impossible to identify any specific genes with a gender difference.

Female↗
PubMed2005

Genomic organization and expression of 23 new genes from MATalpha locus of Cryptococcus neoformans var. gattii.

The pathogenic yeast Cryptococcus neoformans (Cn) causes cryptococcosis, a life-threatening disease of the brain. Molecular studies of Cn variety gattii have lagged behind other two varieties (var. grubii and var. neoformans) although they have distinct biology and disease patterns. We focused on gene discovery in MATalpha locus because it predominates in clinical strains. A var. gattii cosmid library was screened with DNA probes from other two varieties. Two positive clones were sequenced to identify ORFs based on similarities to known proteins, and to ESTs using bioinformatics, and manually by a curator. Approximately 76kb sequenced DNA revealed 23 genes and ORFs. The existence of predicted genes was verified by RT-PCR analyses designed to amplify spliced sequences. The results confirmed that the transcripts were expressed both at 30 and 37 degrees C. The var. gattii MATalpha locus genes showed rearrangements in order and orientation vis-a-vis other two varieties. Mating-specific genes showed higher nonsynonymous mutation rates, and gene trees showed var. gattii strains in a distinct clade. The identification of the largest number, thus far, of var. gattii structural genes should set the stage for future molecular pathogenesis studies.

Chromosome Mapping↗
PubMed2003

STRING: finding tandem repeats in DNA sequences.

MOTIVATION AND RESULTS: The importance of Tandem Repeats in some genomes is now well established. We have reported elsewhere some interesting new results obtained by means of a preliminary program for finding Tandem Repeats in DNA sequences, together with a brief description of the basic ideas of the algorithm. We describe here a completely new program based only in part on those ideas, we briefly discuss the interpretation of the results, and, by way of example, we provide a few novel results relative to the parasites responsible of two re-emerging diseases, Plasmodium falciparum and Mycobacterium tuberculosis. Our program is portable, effective, powerful and fast: it can run on current desktop computers, and it finds all significant Tandem Repeats also in the longest segments of sequences in databases (up to millions of bases), in short times (minutes). AVAILABILITY: An academic version of the algorithm (full source listing in standard C language) can be freely downloaded (http://www.caspur.it/~castri/STRING/). SUPPLEMENTARY INFORMATION: Some illustrative figures and some sample results are provided as supplementary material at: http://www.caspur.it/~castri/STRING/

Algorithms↗
PubMed2002

A genetic and genomic analysis identifies a cluster of genes associated with hematopoietic cell turnover.

Hematopoietic stem cells from different strains of mice vary widely with respect to their cell cycle activity. In the present study we used complementary genetic and genomic approaches to identify molecular pathways affecting this complex trait. We identified a major quantitative trait locus (QTL) associated with variation in cell proliferation in C57BL/6 and DBA/2 mice to a 10 centimorgan (cM) region on chromosome 11. A congenic mouse model confirmed that a genomic interval on chromosome 11 in isolation confers the proliferation phenotype. To detect candidate genes we performed subtractive hybridizations and gene arrays using cDNA from highly enriched stem cells from parental strains. Intriguingly, a disproportionate number of differentially expressed genes mapped to chromosome 11 and, more specifically, these transcripts occurred in 3 distinct clusters. The largest cluster colocalized exactly with the cell cycling QTL. Such clustering suggested the involvement of genetic variation that affects higher-order chromosomal organization. This hypothesis was reinforced by the fact that differentially expressed genes mapped to recombination "coldspots," as a consequence of which clustered genes are collectively inherited. These findings suggest the functional interdependence of these closely linked genes. Our data are consistent with the hypothesis that this isolated cell cycle QTL does not result from a mutation in a single gene but rather is a consequence of variable expression of a collection of highly linked genes.

Animals↗
PubMed2002

Representational difference analysis in a lupus-prone mouse strain results in the identification of an unstable region of the genome on chromosome 11.

BXSB mice develop a lupus-like autoimmune syndrome. We have previously identified several intervals that were linked to disease and, in an attempt to characterise lupus susceptibility genes within these intervals, we have sought to isolate differentially expressed genes. Representational difference analysis was used to compare gene expression between BXSB and C57BL/10 mice using spleen and thymus as a source of mRNA. The majority of differentially expressed sequences identified were immunoglobulin and gp70-related sequences, overexpression of these being characteristic of the disease. Among other isolated sequences were a sialyltransferase gene, a mouse tumour virus superantigen gene (Mtv-3), and the virus-related sequence, hitchhiker. In BXSB the sialyltransferase gene not only overexpressed spliced transcripts, but also produced high levels of unspliced mRNA. Further analysis demonstrated that the copy number of the three linked sequences: sialyltransferase, Mtv-3 and hitchhiker, was amplified in BXSB and that the structural organisation of this locus varies in different mouse strains. This locus consists of three parts, Mtv-3-hitchhiker-sialyltransferase, hitchhiker-sialyltransferase, and sialyltransferase alone. Different combinations of the regions are present in different mouse strains. Linkage analysis demonstrated that this region at the distal end of chromosome 11 is weakly linked to phenotypic markers of disease.

Alternative Splicing↗
PubMed2006

Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display.

Head and neck squamous cell carcinoma (HNSCC) is common worldwide and is associated with a poor rate of survival. Identification of new markers and therapeutic targets, and understanding the complex transformation process, will require a comprehensive description of genome expression, that can only be achieved by combining different methodologies. We report here the HNSCC transcriptome that was determined by exhaustive differential display (DD) analysis coupled with validation by different methods on the same patient samples. The resulting 820 nonredundant sequences were analysed by high throughput bioinformatics analysis. Human proteins were identified for 73% (596) of the DD sequences. A large proportion (>50%) of the remaining unassigned sequences match ESTs (expressed sequence tags) from human tumours. For the functionally annotated proteins, there is significant enrichment for relevant biological processes, including cell motility, protein biosynthesis, stress and immune responses, cell death, cell cycle, cell proliferation and/or maintenance and transport. Three of the novel proteins (TMEM16A, PHLDB2 and ARHGAP21) were analysed further to show that they have the potential to be developed as therapeutic targets.

Amino Acid Sequence↗
PubMed2005

Genome-wide analysis of differentially expressed genes from Penicillium chrysogenum grown with a repressing or a non-repressing carbon source.

Penicillium chrysogenum is an economically important ascomycete used as industrial producer of penicillin. However, with the exception of penicillin biosynthesis genes, little attention has been paid to the genetics of other aspects of the metabolism of this fungus. In this article we describe the first attempt of systematic analysis of expressed genes in P. chrysogenum, using a suppression subtractive hybridization approach to clone and identify sequences of genes differentially expressed in media with glucose or lactose as carbon source (penicillin-repressing or non-repressing conditions). A total of 167 clones were analysed, 95 from the glucose condition and 72 from the lactose condition. Genes differentially expressed in the glucose condition encode mainly proteins involved in the mitochondrial electron transport chain and primary metabolism. Genes expressed differentially in lactose-containing medium include genes for secondary metabolism (pcbC, isopenicillin N synthase), different hydrolases and a gene encoding a putative hexose transporter or sensor. The results provided information on how the metabolism of this fungus adapts to different carbon sources. The expression patterns of some of the genes support the hypothesis that glucose induces higher rates of respiration in P. chrysogenum while repressing secondary metabolism.

Amino Acid Sequence↗
PubMed2006

Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons.

Orthologous gene structures in eight vertebrate species were compared on a genomic scale to detect the birth and maturation of new internal exons during the course of evolution. We found that 40% of new human exons are alternatively spliced, and most of these are cassette exons (exons that are either included or skipped in their entirety) with low inclusion rates. This proportion decreases steadily as older and older exons are examined, even as splicing efficiency increases. Remarkably, the great majority of new cassette exons are composed of highly repeated sequences, especially Alu. Many new cassette exons are 5' untranslated exons; the proportion that code for protein increases steadily with age. New protein-coding exons evolve at a high rate, as evidenced by the initially high substitution rates (K(s) and K(a)), as well as the SNP density compared with older exons. This dynamic picture suggests that de novo recruitment rather than shuffling is the major route by which exons are added to genes, and that species-specific repeats could play a significant role in recent evolution.

Alternative Splicing↗
PubMed2005

Functional genomics of nematode acetylcholinesterases.

Acetylcholine is the major excitatory neurotransmitter controlling motor activities in nematodes, and the enzyme which hydrolyses and inactivates acetylcholine, acetylcholinesterase, is thus essential for regulation of cholinergic transmission. Different forms of acetylcholinesterase are encoded by multiple genes in nematodes, and analysis of the pattern of expression of these genes in Caenorhabditis elegans suggests that they perform non-redundant functions. In addition, many parasitic species which colonise host mucosal surfaces secrete hydrophilic variants of acetylcholinesterase, although the function of these enzymes is still unclear. Acetylcholinesterases have a history as targets for therapeutic agents against helminth parasites, but anti-cholinesterases have been used much more extensively as pesticides, for example to control crop damage and ectoparasitic infestation of livestock. The toxicity associated with these compounds (generally organophosphates and carbamates) has led to legislation to withdraw them from the market or restrict their use in many countries. Nevertheless, acetylcholinesterases provide a good example of a neuromuscular target enzyme in helminth parasites, and it may yet be possible to develop more selective inhibitors. In this article, we describe what is known about the structure and function of vertebrate cholinesterases, illustrate the molecular diversity and tissue distribution of these enzymes in C. elegans, and discuss to what extent this may represent a paradigm for nematodes in general.

Acetylcholinesterase↗
PubMed2005

Disruption of TCBA1 associated with a de novo t(1;6)(q32.2;q22.3) presenting in a child with developmental delay and recurrent infections.

A boy with developmental delay, particularly of speech, a distinct face, antineutrophil cytoplasmic antibodies, and recurrent infections was found to have an apparently balanced de novo t(1;6)(q32.3;q22.3) translocation. Fluorescent in situ hybridisation with BAC/PAC clones and long range polymerase chain reaction products assessed in the human genome sequence localised the chromosome 1 breakpoint to a 9.8 kb segment within a hypothetical gene, LOC388735, and the chromosome 6 breakpoint to a 12.8 kb segment in intron 4 of the T-cell lymphoma breakpoint-associated target 1 (TCBA1) gene. Disruption and/or formation of TCBA1 fusion genes in T cell lymphoma and leukaemia cell lines suggests a role for this gene in tumorigenesis. The isolated mouse Tcba1 gene shows 91% amino acid sequence similarity with human TCBA1. It is expressed in fetal and adult brain and with lower levels in liver and testis. The human gene has been reported to be expressed exclusively in brain and thymus. Reduced TCBA1 expression in brain and thymus may explain at least some of the symptoms in this patient. It is concluded that germline alterations of the TCBA1 gene are associated with developmental delay and typical physical features.

Amino Acid Sequence↗
PubMed2006

Nonribosomal peptide synthetase (NPS) genes in Fusarium graminearum, F. culmorum and F. pseudograminearium and identification of NPS2 as the producer of ferricrocin.

Fungi have the potential to produce a wide range of secondary metabolites including polyketides and small peptides produced by nonribosomal peptide synthetases (NPS). Fusarium graminearum is a mycotoxin producing pathogen of cereals and knowledge of the infection process is essential for the development of disease control. Bioinformatics provide a means to identify genes encoding NPSs, the products of which may act as fungal virulence factors. The F. graminearum genome sequence was analysed and similarity searches and application of prediction server service identified 15 putative NPS genes. NPS1 and NPS2, were found to be related to genes involved in NPS hydroxamate siderophore biosynthesis and chemical analysis of a F. graminearum NPS2 deletion mutant showed that this gene encodes the NPS responsible for the biosynthesis of ferricrocin. The expression of the NPS genes was analysed in Fusarium culmorum. NPS1 and NPS19 differed from the remainder of the genes, as they were only expressed during infection of barley roots and not under the different culture conditions tested. Strains of F. graminearum, F. culmorum and Fusarium pseudograminearum were examined for the presence and expression of the 15 identified NPS genes. With the exception of NPS18, that is absent in F. pseudograminearum, all the NPS genes are represented in the diffferent species. Lack of transcripts from some genes and the presence of frameshift and stop codons in four of the NPS genes in the sequenced F. graminearum strain suggest that some are pseudogenes.

Ferrichrome↗
PubMed2004

The Use of DNA Microarrays to Investigate the Pharmacogenomics of Drug Response in Living Systems

With the advent of DNA microarray analysis, it is now possible to examine the response of virtually the entire human genome to cellular drug exposure and to uncover a wide variety of genes correlating with the establishment of drug resistance. This relatively new field of "pharmacogenomics" is likely to vastly increase our understanding of the mechanisms of drug action and how cells respond and adapt to drug exposure. However, DNA microarray studies typically result in the identification of hundreds of genes that may or may not be of relevance in vivo-particularly when large, genetically diverse study populations are used. The challenge to the researcher is to design experimental systems and approaches which minimize variability in the data, increase the reproducibility amongst experiments, allow array data from multiple experiments to be assessed by a variety of statistical, supervised learning, and data clustering approaches, and provide a clear link between drug response and the expression of specific genes. This review provides a description and critical analysis of recent studies on the pharmacogenomics of drug response and discusses current guidelines and approaches for the performance and analysis of DNA microarray experiments in this area.

Animals↗
PubMed2006

Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells.

WNT, Notch, FGF, and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. Association of Notch ligands with Notch receptors on neighboring cells leads to cleavage of Notch receptors by metalloprotease and gamma-secretase to induce nuclear translocation of Notch intracellular domain (NICD). Nuclear complex, consisting of CSL (RBPSUH), NICD, Mastermind (MAML), p300 and histone acetyltransferase (HAT), then induces transcriptional activation of Notch target genes, such as HES1, HES5, HES7, HEY1, HEY2 and HEYL. Here, we searched for TCF/LEF-binding site within the promoter region of Notch ligand genes, including DLL1, DLL3, DLL4, JAG1 and JAG2. Because TCF/LEF-binding sites were identified within human JAG1 promoter based on bioinformatics and human intelligence, comparative genomics analyses on JAG1 orthologs were further performed. Chimpanzee JAG1 gene, consisting of 26 exons, was identified within NW_120319.1 genome sequence. XM_525264.1 and XM_514517.1 were not the correct coding sequences for chimpanzee JAG1. Chimpanzee JAG1 gene was found to encode a 1218-amino-acid protein showing 99.5% and 96.2% total-amino-acid identity with human JAG1 and mouse Jag1, respectively. Phylogenetic analysis revealed that JAG1 orthologs were more conserved than those of other Notch ligands. JAG1 gene was identified as evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian JAG1 orthologs. Human JAG1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, lung carcinoid, gastric cancer, pancreatic cancer, colon cancer, and also in squamous cell carcinoma (SCC) of skin, oral cavity, esophagus, head and neck. JAG1 expression on progenitor cells due to canonical WNT signaling activation induces self-renewal of stem cells due to Notch signaling activation. JAG1, functioning as WNT-dependent Notch signaling activator, is the key molecule maintaining the homeostasis of stem and progenitor cells.

Amino Acid Sequence↗
PubMed2004

A genomic- and proteomic-based hypothesis on the eclectic effects of systemic interleukin-2 administration in the context of melanoma-specific immunization.

Among human cancers, melanoma is characterized by an almost unique predisposition to regress in response to immune therapy. Recent clinical studies suggest that the frequency of this favorable event is enhanced by combining T-cell-directed active specific immunization with the systemic administration of interleukin (IL)-2. While waiting for additional clinical experience to confirm this observation, we embraced the working hypothesis that this combination provides superior response rates than either treatment alone. In particular, we have focused our interest on the paradoxical observation that active specific immunization consistently induces circulating CD8+ T cells capable of recognizing in ex vivo assays tumor cells, but cannot induce tumor regression alone. In these settings, it appears that combining the systemic administration of IL-2 is almost an absolute requirement for the induction of clinical responses. Here, we will expand on previous speculations on the postulated mechanism(s) of action of systemic IL-2 administration and, based on original data recently derived through high-throughput transcriptional and post-translational analysis, we will suggest an explanation for the eclectic effects of IL-2 administration in the context of active specific immunization.

CD8-Positive T-Lymphocytes↗
PubMed2002

Renal transcriptomes: segmental analysis of differential expression.

BACKGROUND/AIMS: Progress accomplished by complete genomes and cDNA-sequencing projects calls for methods that fully use these resources to study gene expression patterns in characterized cell populations. However, since the number of functional genes cannot be readily inferred from the genomic sequence, it is highly desirable to make use of methods enabling to study both known and unknown genes. METHODS: The method of serial analysis of gene expression provides short diagnostic cDNA tags without bias towards known genes. In addition, the frequency of each tag in the library conveys quantitative information on gene expression. A microassay was set-up to perform serial analysis of gene expression in minute samples such as those obtained by microdissecting nephron segments. RESULTS: Studies carried out in the thick ascending limb of Henle's loop and the collecting duct of the mouse kidney provided expression data for several thousand genes. Known markers were found appropriately enriched, and several of the thick ascending limb or collecting duct specific transcripts had no database match. CONCLUSIONS: The microassay for serial analysis of gene expression makes possible large-scale quantitative measurements of mRNA levels in nephron segments. The comprehensive picture generated by analyzing both known and unknown transcripts in defined cell populations should help to discover genes with dedicated functions.

Animals↗
PubMed2004

Application of comparative functional genomics to identify best-fit mouse models to study human cancer.

Genetically modified mice have been extensively used for analyzing the molecular events that occur during tumor development. In many, if not all, cases, however, it is uncertain to what extent the mouse models reproduce features observed in the corresponding human conditions. This is due largely to lack of precise methods for direct and comprehensive comparison at the molecular level of the mouse and human tumors. Here we use global gene expression patterns of 68 hepatocellular carcinomas (HCCs) from seven different mouse models and 91 human HCCs from predefined subclasses to obtain direct comparison of the molecular features of mouse and human HCCs. Gene expression patterns in HCCs from Myc, E2f1 and Myc E2f1 transgenic mice were most similar to those of the better survival group of human HCCs, whereas the expression patterns in HCCs from Myc Tgfa transgenic mice and in diethylnitrosamine-induced mouse HCCs were most similar to those of the poorer survival group of human HCCs. Gene expression patterns in HCCs from Acox1(-/-) mice and in ciprofibrate-induced HCCs were least similar to those observed in human HCCs. We conclude that our approach can effectively identify appropriate mouse models to study human cancers.

Animals↗
PubMed2006

Symmetric time warping, Boltzmann pair probabilities and functional genomics.

Given two time series, possibly of different lengths, time warping is a method to construct an optimal alignment obtained by stretching or contracting time intervals. Unlike pairwise alignment of amino acid sequences, classical time warping, originally introduced for speech recognition, is not symmetric in the sense that the time warping distance between two time series is not necessarily equal to the time warping distance of the reversal of the time series. Here we design a new symmetric version of time warping, and present a formal proof of symmetry for our algorithm as well as for one of the variants of Aach and Church [1]. We additionally design quadratic time dynamic programming algorithms to compute both the forward and backward Boltzmann partition functions for symmetric time warping, and hence compute the Boltzmann probability that any two time series points are aligned. In the future, with the availability of increasingly long and accurate time series gene expression data, our algorithm can provide a sense of biological significance for aligned time points - e.g. our algorithm could be used to provide evidence that expression values of two genes have higher Boltzmann probability (say) in the G1 and S phase than in G2 and M phases. Algorithms, source code and web interface, developed by the first author, are made publicly available via the Boltzmann Time Warping web server at bioinformatics.bc.edu/clotelab/.

Algorithms↗