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PubMed2004

Selective gene expression in multigene families from yeast to mammals.

Exclusive gene expression, where only one member of a gene or gene cassette family is selected for expression, plays an important role in the establishment of cell identity in several biological systems. Here, we compare four such systems: mating-type switching in fission and budding yeast, where cells choose between expressing one of the two different mating-type cassettes, and immunoglobulin and odorant receptor gene expression in mammals, where the number of gene choices is substantially higher. The underlying mechanisms that establish this selective expression pattern in each system differ in almost every detail. In all four systems, once a successful gene activation event has taken place, a feedback mechanism affects the fate of the cell. In the mammalian systems, feedback is mediated by the expressed cell surface receptor to ensure monoallelic gene expression, whereas in the yeasts, the expressed gene cassette at the mating-type locus affects donor choice during the subsequent switching event.

Animals↗
PubMed2003

Selective gene regulation with designed transcription factors: implications for therapy.

The prospect of selectively regulating gene expression is highly appealing, both for laboratory investigations and for potential therapeutic applications. This possibility has recently become a reality through the use of designed transcription factors (DTFs). This approach makes use of the DNA-binding domains of native transcription factors as scaffolds, but then introduces new DNA recognition capabilities that allow selective recognition of the regulatory regions of individual genes. The DTF strategy allows either upregulation or downregulation of transcription. This differs from approaches such as antisense or RNA interference that are intended only to inhibit gene expression. Much of the work to date on DTFs has exploited the modular nature of Cys2-His2 zinc finger (Zif) modules that, when coupled with the use of phage display or other combinatorial library techniques, allow the creation of novel and selective DNA recognition domains. These domains can then be linked to transcriptional regulatory moieties, including transactivator or repressor domains, to modulate gene expression. Recent progress has demonstrated that DTFs can selectively regulate the transcription of endogenous genes in mammalian cells and in living animals.

Adenoviridae↗
PubMed2004

Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes.

We developed concise, accurate prediction models of the in vitro activity for 8 anticancer drugs (5-FU, CDDP, MMC, DOX, CPT-11, SN-38, TXL and TXT), along with individual clinical responses to 5-FU using expression data of 12 genes. We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes. The correlation significance of each was confirmed using expression data quantified by real-time RT-PCR, and finally 12 genes (ABCB1, ABCG2, CYP2C8, CYP3A4, DPYD, GSTP1, MGMT, NQO1, POR, TOP2A, TUBB and TYMS) were selected as more reliable predictors of drug response. Using multiple regression analysis, we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order, to predict the efficacy of the drugs by referring to the value of Akaike's information criterion for each sample. These formulae appeared to accurately predict the in vitro efficacy of the drugs. For the first clinical application model, we fixed prediction formulae for individual clinical response to 5-FU in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival, time to treatment failure and tumor growth. None of the 12 selected genes alone could predict such clinical responses.

Antimetabolites, Antineoplastic↗
PubMed2006

Expression profilings of 39 genes selected by ANOVA could separate precursors of murine dendritic cells and macrophages.

Dendritic cells (DCs) and macrophages share some stages in the development and function of antigen presentation. But it is difficult to separate them from their precursors. We used one-way ANOVA (analysis of variances) on murine expression profilings of several hematopoietic cells associated with DCs and macrophages to find the genes with great differences across the cell groups. These groups were the DCs from spleen, cultivated DCs, DC precursors, DC progenitors, DC progenitor cell lines, hematopoietic stem cell (HSC), and bone marrow-derived macrophages. The data of expression profilings were all downloaded from GEO and ArrayExpress database. After the normalization of 11 housekeeping genes across 42 arrays, we got 39 genes (44 probesets) by analysis of one-way ANOVA (Bonferroni step-down) with p values cutoff of 0.05. These genes (probesets) could separate the hematopoietic cells well by the methods of unsupervised hierarchical clustering and principal component analysis (PCA). The class prediction also indicated that these genes could separate the precursors of DC and macrophages with 20 arrays composed of 5 cell types with the same normalization. The accuracy rate of class prediction was 90% (18/20). The genes selected by one-way ANOVA included those of MHC (major histocompatibility complex) and defense of immunity, cell adhesion, chemokine or its receptors, and transcription factors. The results indicated that these 39 genes could separate precursors of DC and macrophages very clearly. It was suggested that these genes might represent some important molecules that related with the precursors of DCs and macrophages, and were worthy for further study.

Animals↗
PubMed2005

Optimized between-group classification: a new jackknife-based gene selection procedure for genome-wide expression data.

BACKGROUND: A recent publication described a supervised classification method for microarray data: Between Group Analysis (BGA). This method which is based on performing multivariate ordination of groups proved to be very efficient for both classification of samples into pre-defined groups and disease class prediction of new unknown samples. Classification and prediction with BGA are classically performed using the whole set of genes and no variable selection is required. We hypothesize that an optimized selection of highly discriminating genes might improve the prediction power of BGA. RESULTS: We propose an optimized between-group classification (OBC) which uses a jackknife-based gene selection procedure. OBC emphasizes classification accuracy rather than feature selection. OBC is a backward optimization procedure that maximizes the percentage of between group inertia by removing the least influential genes one by one from the analysis. This selects a subset of highly discriminative genes which optimize disease class prediction. We apply OBC to four datasets and compared it to other classification methods. CONCLUSION: OBC considerably improved the classification and predictive accuracy of BGA, when assessed using independent data sets and leave-one-out cross-validation. AVAILABILITY: The R code is freely available [see Additional file 1] as well as supplementary information [see Additional file 2].

Algorithms↗
PubMed2002

Use of differential display-polymerase chain reaction to identify genes selectively modulated by chemical allergens in reconstituted human epidermis.

In the screening of topical drugs, cosmetics and other chemicals for human use, it is very important, both from a safety and an economic point of view, to have biological markers to discriminate irritant and allergic contact dermatitis that have different impacts on human health. Owing to their anatomical location, keratinocytes are among the first cells to be exposed to various antigens and the use of these cells as a simplified in vitro model to evaluate the potential toxicity of chemicals destined for cutaneous application is amply justified. The purpose of this work was to identify new genes selectively modulated by skin toxicants. Commercially available reconstituted human epidermis (Epiderm) was treated for 18 h with sodium dodecyl sulfate (SDS) 0.4 mg/ml, as reference irritant, or with dinitrochlorobenzene (DNCB) 0.2 mg/ml, as reference allergen, or with vehicle control. Differential display PCR (DD-PCR) was performed. Results identified adipose differentiation-related protein (ADRP) as up-regulated by both irritant and allergen, and KIAA0368 as selectively up-regulated by contact allergen. These data indicate the enormous potential of functional genomic techniques, which allow the identification of genes not immediately connected with the immune response, or even novel genes with unknown functions, which nevertheless may be potential markers of skin irritation and allergy.

Allergens↗
PubMed2003

A simple and efficient algorithm for gene selection using sparse logistic regression.

MOTIVATION: This paper gives a new and efficient algorithm for the sparse logistic regression problem. The proposed algorithm is based on the Gauss-Seidel method and is asymptotically convergent. It is simple and extremely easy to implement; it neither uses any sophisticated mathematical programming software nor needs any matrix operations. It can be applied to a variety of real-world problems like identifying marker genes and building a classifier in the context of cancer diagnosis using microarray data. RESULTS: The gene selection method suggested in this paper is demonstrated on two real-world data sets and the results were found to be consistent with the literature. AVAILABILITY: The implementation of this algorithm is available at the site http://guppy.mpe.nus.edu.sg/~mpessk/SparseLOGREG.shtml SUPPLEMENTARY INFORMATION: Supplementary material is available at the site http://guppy.mpe.nus.edu.sg/~mpessk/SparseLOGREG.shtml

Algorithms↗
PubMed2003

Mycobacterium tuberculosis exerts gene-selective inhibition of transcriptional responses to IFN-gamma without inhibiting STAT1 function.

Mycobacterium tuberculosis is a highly successful human pathogen. A major component of this success is the pathogen's ability to avoid eradication by the innate and adaptive immune responses throughout the course of infection. IFN-gamma, a potent activator of the microbicidal activities of macrophages, is essential for control of M. tuberculosis infection, but is unable to stimulate macrophages to kill M. tuberculosis. We have found that infection of the human monocytic cell line, THP-1, resulted in reduced cellular responses to IFN-gamma, manifested as impaired induction of CD64 surface expression and transcription. This defect in transcription occurred despite normal activation of STAT1 in infected macrophages: there was no decrease in STAT1 tyrosine or serine phosphorylation, nuclear translocation, or binding of a minimal IFN-gamma response sequence. Assays of STAT1 function in M. tuberculosis-treated cells also revealed no defect in activation of a minimal gamma-activated sequence construct or STAT1 recruitment to and binding at the endogenous CD64 promoter. In addition, M. tuberculosis did not affect histone acetylation at the CD64 promoter. The inhibition of transcription was gene selective: while transcription of CD64 and class II transactivator were decreased, certain other IFN-gamma-responsive genes either were unaffected or were increased by M. tuberculosis. These results indicate that M. tuberculosis inhibits the response to IFN-gamma by a mechanism distinct from either suppressor of cytokine signaling-1 inhibition of STAT1 phosphorylation or protein inhibitor of activated STAT interference with DNA binding, and indicate that other mechanisms of inhibition of IFN-gamma responses remain to be discovered.

DNA-Binding Proteins↗
PubMed2006

Selective gene transfer to T lymphocytes using coreceptor-specific [MLV(HIV)] pseudotype vectors in a transgenic mouse model.

The coreceptor usage of HIV-1 envelope proteins (Env) is mainly dependent on a defined variable region within the V3-loop of Env. Thus, retroviral vectors derived from murine leukemia virus (MLV), which have been pseudotyped with HIV-1 envelope proteins holding different V3-loops, enable selective gene delivery into either CXCR4 or CCR5 positive cultured cells. Here, we tested the distribution of CD4/CCR5-tropic [MLV(HIV)]-pseudotype vectors in transgenic mice expressing CD4 and either CXCR4 or CCR5 of human origin. The specificity of gene transfer was analyzed by ex vivo transduction of spleen cells as well as after i.v. or i.p. injection of transgenic mice. Expression of the transferred marker gene EGFP and vector sequences could be detected exclusively in lymphocytes expressing (hu)CD4 and (hu)CCR5, whereas MLV vectors pseudotyped with the VSV-G envelope glycoprotein mediated gene transfer in mice of all genotypes investigated. These data demonstrated that cell-specific gene delivery via [MLV(HIV)]-pseudotyped vectors, as previously shown for cultured cells, is also achievable in vivo.

Animals↗
PubMed1997

Micronuclei containing whole chromosomes harbouring the selectable gene do not lead to mutagenesis.

Loss of heterozygosity is one genetic change observed in many tumours. We do not know whether the loss of chromosomal material through micronucleus formation is a viable mechanism associated with, and possibly leading to, genetic disease. Previously, we treated L5178Y mouse lymphoma cells with four aneugens. Although these aneugens induced micronuclei containing predominantly whole chromosomes, they did not induce mutations at Tk1, the selectable gene, under the same non-toxic conditions in which they induced micronuclei. This suggested that the induction of micronuclei containing whole chromosomes was not an early event leading to phenotypically expressed mutations in these cells under the conditions used. However, it is possible that chromosome 11, on which Tk1 resides, may be under-represented in the micronucleus population. To find out the frequency of induction of micronuclei containing chromosome 11, we applied fluorescence in situ hybridization using a chromosome 11 paint to micronuclei induced by colcemid and vinblastine. We found that the numbers of micronuclei containing chromosome 11 are more than sufficient to be detectable as mutations if these micronuclei lead to viable mutants. We conclude that the formation of micronuclei containing whole chromosomes does not lead to viable, dividing mutants in this system.

Animals↗
PubMed1996

IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes.

Interaction of IL-10 with its receptor leads to the activation of STAT transcription factors. Herein we report the IL-10 dependent simultaneous activation of three STAT transcription factors: Stat1, Stat3, and Stat5. Upon IL-10 treatment multiple Stat proteins become simultaneously activated, and bind to different promoters with equal kinetics but form distinct homo- and heterodimeric transcriptionally active complexes depending on the STAT-consensus elements of a selected gene promoter. Upon IL-10 treatment Stat1, 3, and 5 bind to the GRR of the FcgammaRI gene, activated Stat1 and 3 bind to the SIE sequence of the c-fos promoter and transcriptionally active Stat5 assembles at the PRL-STAT consensus sequence of the beta-casein gene. Thus, functionally relevant STAT dimerization is influenced by the activated cytokine receptor as well as the specific STAT consensus sequence present in a specific gene promoter.

B-Lymphocytes↗
PubMed2005

Unilateral kidney-selective gene transfer following the administration of naked plasmid DNA to the kidney surface in mice.

We developed a gene transfer following the administration of naked plasmid DNA (pDNA) to the kidney surface in mice, and found that the luciferase levels produced in the applied kidney were significantly higher than those produced in another kidney. In contrast, stable renal gene expression was not observed in the case of intraperitoneal or intravenous administration of pDNA. The level of gene expression after instillation of pDNA to the kidney surface reached maximum at 12 h and gradually diminished thereafter. The production of luciferase was saturated at 5 microg of pDNA, and was not affected by instillation volume. Furthermore, pDNA uptake from the kidney surface was proved by in situ experiments using a glass-made diffusion cell. We demonstrated a novel unilateral kidney-selective gene transfer following the administration of naked pDNA to the kidney surface in mice.

Animals↗
PubMed2006

Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins.

Neuroligins 1-4 are postsynaptic transmembrane proteins capable of initiating presynaptic maturation via interactions with beta-neurexin. Both neuroligins and beta-neurexins have alternatively spliced inserts in their extracellular domains. Using analytical ultracentrifugation, we determined that the extracellular domains of the neuroligins sediment as dimers, whereas the extracellular domains of the beta-neurexins appear monomeric. Sedimentation velocity experiments of titrated stoichiometry ratios of beta-neurexin and neuroligin suggested a 2:2 complex formation. The recognition properties of individual neuroligins toward beta-neurexin-1 (NX1beta), along with the influence of their splice inserts, were explored by surface plasmon resonance and affinity chromatography. Different neuroligins display a range of NX1beta affinities spanning more than 2 orders of magnitude. Whereas splice insert 4 in beta-neurexin appears to act only as a modulator of the neuroligin/beta-neurexin association, splice insert B in neuroligin-1 (NL1) is the key element regulating the NL1/NX1beta binding. Our data indicate that gene selection, mRNA splicing, and post-translational modifications combine to give rise to a controlled neuroligin recognition code with a rank ordering of affinities for particular neurexins that is conserved for the neuroligins across mammalian species.

Alternative Splicing↗
PubMed2000

Comparing sequenced segments of the tomato and Arabidopsis genomes: large-scale duplication followed by selective gene loss creates a network of synteny.

A 105-kilobase bacterial artificial chromosome (BAC) clone from the ovate-containing region of tomato chromosome 2 was sequenced and annotated. The tomato BAC sequence was then compared, gene by gene, with the sequenced portions of the Arabidopsis thaliana genome. Rather than matching a single portion of the Arabidopsis genome, the tomato clone shows conservation of gene content and order with four different segments of Arabidopsis chromosomes 2-5. The gene order and content of these individual Arabidopsis segments indicate that they derived from a common ancestral segment through two or more rounds of large-scale genome duplication events-possibly polyploidy. One of these duplication events is ancient and may predate the divergence of the Arabidopsis and tomato lineages. The other is more recent and is estimated to have occurred after the divergence of tomato and Arabidopsis approximately 112 million years ago. Together, these data suggest that, on the scale of BAC-sized segments of DNA, chromosomal rearrangements (e.g., inversions and translocations) have been only a minor factor in the divergence of genome organization among plants. Rather, the dominating factors have been repeated rounds of large-scale genome duplication followed by selective gene loss. We hypothesize that these processes have led to the network of synteny revealed between tomato and Arabidopsis and predict that such networks of synteny will be common when making comparisons among higher plant taxa (e.g., families).

Arabidopsis↗
PubMed2001

Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.

Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie/adenovirus receptor (CAR), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor-specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule (EpCAM) between normal and (pre)malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber-knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM-targeted vectors. This study thus indicates that EpCAM-targeted adenoviral vectors may be useful for gastric and esophageal cancer-specific gene therapy in patients.

Adenocarcinoma↗
PubMed2005

Multiple SVM-RFE for gene selection in cancer classification with expression data.

This paper proposes a new feature selection method that uses a backward elimination procedure similar to that implemented in support vector machine recursive feature elimination (SVM-RFE). Unlike the SVM-RFE method, at each step, the proposed approach computes the feature ranking score from a statistical analysis of weight vectors of multiple linear SVMs trained on subsamples of the original training data. We tested the proposed method on four gene expression datasets for cancer classification. The results show that the proposed feature selection method selects better gene subsets than the original SVM-RFE and improves the classification accuracy. A Gene Ontology-based similarity assessment indicates that the selected subsets are functionally diverse, further validating our gene selection method. This investigation also suggests that, for gene expression-based cancer classification, average test error from multiple partitions of training and test sets can be recommended as a reference of performance quality.

Algorithms↗
PubMed1984

Introduction of a selectable gene into different animal tissue by a retrovirus recombinant vector.

The potential use of retrovirus vectors to transduce foreign genetic information into cells of different tissues of an animal was explored by introducing a recombinant genome carrying the Eco gpt gene into postimplantation mouse embryos. To obviate the need for preparing concentrated virus stocks, psi 2-2-5 cells producing the replication-defective murine sarcoma virus (MSV)-gpt virus were microinjected directly into embryos. The psi 2-2-5 cells were mixed with cells producing replication-competent Moloney murine leukemia virus (Mo-MuLV) to facilitate spread of the vector. A high percentage of the manipulated embryos continued to develop without disturbance and were analyzed either prior to birth or as adults for expression of both helper and Eco gpt virus. Microinjection of as few as 10 Mo-MuLV-producing cells resulted in viremia of greater than 50% of the embryos or adults, 25%-30% of which produced MSV-gpt recombinant virus in a variety of organs including thymus, spleen, lung, kidney, and brain. The fraction of vector-producing cells, however, was 3 to 5 orders of magnitude lower than that of helper-virus-producing cells. Our results demonstrate that a selectable gene can be introduced by retroviral vectors into animals and can be expressed in a wide variety of different somatic tissues.

Animals↗
PubMed2003

A set of genes selectively expressed in murine dendritic cells: utility of related cis-acting sequences for lentiviral gene transfer.

Professional antigen presenting cells such as dendritic cells (DC) and macrophages (Mphi) share similar characteristics; however, they differ in their ability to initiate an immune response. DCs are much more potent in priming and stimulating nai;ve T-cells. Thus, DCs are good targets for the expression of foreign genes to elicit and specifically modify immune responses. To identify DC markers cDNA subtraction was performed using murine MHC class II(high), B7(high) bone marrow derived DCs as tester and interferon-gamma/E. coli lipopolysaccaride (LPS) treated bone marrow derived macrophages as driver. Analysis of 114 resulting clones revealed a diverse pattern of DC selective (DC(DeltaMphi)) gene expression including known genes whose expression in DCs had not been previously demonstrated as well as multiple novel genes. For several identified DC(DeltaMphi) genes, proximal promoter elements were isolated and incorporated into self-inactivating lentiviral GFP reporter vectors. Promoter activity was measured in bone marrow derived macrophages or dendritic cells. Of the promoters analyzed those for B7-DC and CCL17 drove strong GFP expression in DCs but not in resting or activated macrophages. The CCL17 promoter offered the highest level of expression in DCs and was further activated by culture with LPS or interleukin-4 (IL-4). In contrast, the B7-DC promoter was induced by IL-4 but not by LPS. Endogenous CCL17 and B7-DC mRNAs were increased similarly in IL-4 cultured DCs but only CCL17 was induced by LPS. Additionally, IL-4 increased cell surface expression of B7-DC in both immature and mature DCs.

Animals↗