Radiation-induced gene translation profiles reveal tumor type and cancer specific components
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Kumaraswamy S
PROVIDER: S-ECPF-GEOD-10547 | biostudies-other | 2008 May
REPOSITORIES: biostudies-other
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Project description:The microarray analysis of total cellular RNA is a common method used in the evaluation of radiation-induced gene expression. However, profiling the cellular transcriptome does not take into account posttranscriptional processes that affect gene expression. To better define the genes whose expression is influenced by ionizing radiation, we used polysome-bound RNA to generate gene translation profiles for a series of tumor and normal cell lines. Cell lines were exposed to 2 Gy, polysome-bound RNA isolated 6 hours later, and then subjected to microarray analysis. To identify the genes whose translation was affected by radiation, the polysome-bound RNA profiles were compared with their corresponding controls using significance analysis of microarrays (<1% false discovery rate). From the statistically significant genes identified for each cell line, hierarchical clustering was performed by average linkage measurement and Pearson's correlation metric. Ingenuity Pathway Analysis was used for distributing genes into biological networks and for evaluation of functional significance. Radiation-induced gene translation profiles clustered according to tissue of origin; the cell lines corresponding to each tissue type contained a significant number of commonly affected genes. Network analyses suggested that the biological functions associated with the genes whose translation was affected by radiation were tumor type-specific. There was also a set of genes/networks that were unique to tumor or normal cells. These results indicate that radiation-induced gene translation profiles provide a unique data set for the analysis of cellular radioresponse and suggest a framework for identifying and targeting differences in the regulation of tumor and normal cell radiosensitivity.
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Project description:The goal of this study was to compare the radiation-induced gene translation profiles generated from human tumor cell lines that are treated with radiation. Keywords: stimulus or stress design A panel of cell lines included 5 gliomas, 4 pancreatic carcinomas, 3 breast carcinomas and 2 non-small cell lung carcinomas. In addition, radiation-induced gene translation profiles were generated for 4 normal human cell lines: a skin fibroblast (BJ), 2 lung fibroblasts (MRC5, MRC9) and mammary epithelial (MEC). Specifically, cell lines were exposed to 2 Gy or sham irradiated, polysome-bound RNA was isolated 6h later and subjected to microarray analyses. Each cell line was evaluated in biological replicates.
2010-07-20 | E-GEOD-10547 | biostudies-arrayexpress
Project description:The goal of this study was to compare the radiation-induced gene translation profiles generated from human tumor cell lines that are treated with radiation. Keywords: stimulus or stress design
2008-04-15 | GSE10547 | GEO
Project description:Flowering is an integral part of the life cycle of flowering plants, which is essential for plant survival and crop production. Most woody fruit trees such as apples and pears bloom in spring, but loquat blooms in autumn and winter. Gibberellin (GA) plays a key role in the regulation of plant flower formation. In this study, we sprayed loquat plants with exogenous GA3, which resulted in vigorous vegetative growth rather than floral bud formation. We then performed a comprehensive RNA-seq analysis on GA3-treated and control-treated leaves and buds over three time periods to observe the effects of exogenous GA3 application on floral initiation and development. The results showed that 111 differentially expressed genes (DEGs) and 563 DEGs were down-regulated, and 151 DEGs and 506 DEGs were up-regulated in buds and leaves, respectively, upon treatment with GA3. Among those that are homologs of the DELLA-mediated GA signal pathway genes, some may be involved in the positive regulation of flower development, including EjWRKY75, EjFT, EjSOC1, EjAGL24, EjSPL, EjLFY, EjFUL, and EjAP1; while some may be involved in the negative regulation of flower development, including EjDELLA, EjMYC3, EjWRKY12, and EjWRKY13. Finally, by analyzing the co-expression of DEGs and key floral genes EjSOC1s, EjLFYs, EjFULs, EjAP1s, 330 candidate genes that may be involved in the regulation of loquat flowering were screened. These genes belong to 74 gene families, including Cyclin_C, Histone, Kinesin, Lipase_GDSL, MYB, P450, Pkinase, Tubulin, and ZF-HD_dimer gene families. These findings provide new insights into the regulation mechanism of loquat flowering.
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Project description:PurposeFibroblasts are considered to play a major role in the development of fibrotic reaction after radiotherapy and premature radiation-induced differentiation has been proposed as a cellular basis. The purpose was to relate gene expression profiles to radiation-induced phenotypic changes of human skin fibroblasts relevant for radiogenic fibrosis.Materials and methodsExponentially growing or confluent human skin fibroblast strains were irradiated in vitro with 1-3 fractions of 4 Gy X-rays. The differentiated phenotype was detected by cytomorphological scoring and immunofluorescence microscopy. Microarray analysis was performed on Human Genome U133 plus2.0 microarrays (Affymetrix) with JMP Genomics software, and pathway analysis with Reactome R-package. The expression levels and kinetics of selected genes were validated with quantitative real-time PCR (qPCR) and Western blotting.ResultsIrradiation of exponentially growing fibroblast with 1 × 4 Gy resulted in phenotypic differentiation over a 5-day period. This was accompanied by downregulation of cell cycle-related genes and upregulation of collagen and other extracellular matrix (ECM)-related genes. Pathway analysis confirmed inactivation of proliferation and upregulation of ECM- and glycosaminoglycan (GAG)-related pathways. Furthermore, pathways related to inflammatory reactions were upregulated, and potential induction and signaling mechanisms were identified. Fractionated irradiation (3 × 4 Gy) of confluent cultures according to a previously published protocol for predicting the risk of fibrosis after radiotherapy showed similar downregulation but differences in upregulated genes and pathways.ConclusionGene expression profiles after irradiation of exponentially growing cells were related to radiation-induced differentiation and inflammatory reactions, and potential signaling mechanisms. Upregulated pathways by different irradiation protocols may reflect different aspects of the fibrogenic process thus providing a model system for further hypothesis-based studies of radiation-induced fibrogenesis.
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Project description:All living organisms are subject to the aging process and experience the effect of ionizing radiation throughout their life. There have been a number of studies that linked ionizing radiation process to accelerated aging, but comprehensive signalome analysis of both processes was rarely conducted. Here we present a comparative signaling pathway based analysis of the transcriptomes of fibroblasts irradiated with different doses of ionizing radiation, replicatively aged fibroblasts and fibroblasts collected from young, middle age and old patients. We demonstrate a significant concordance between irradiation-induced and replicative senescence signalome signatures of fibroblasts. Additionally, significant differences in transcriptional response were also observed between fibroblasts irradiated with high and low dose. Our data shows that the transcriptome of replicatively aged fibroblasts is more similar to the transcriptome of the cells irradiated with 2 Gy, than with 5 ?Gy.This work revealed a number of signaling pathways that are shared between senescence and irradiation processes and can potentially be targeted by the new generation of gero- and radioprotectors.
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Project description:Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ?30 - 40% were common to all treatment conditions and ?5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles, paralleling responses to adjuvant-containing vaccines in vivo Age-specific in vitro modeling coupled with proteomics may provide fresh insight into the ontogeny of adjuvant action thereby informing targeted adjuvanted vaccine development for distinct age groups.
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Project description:The dimorphic fungus Histoplasma capsulatum causes respiratory and systemic disease in mammalian hosts by expression of factors that enable survival within phagocytic cells of the immune system. Histoplasma's dimorphism is distinguished by growth either as avirulent mycelia or as pathogenic yeast. Geographically distinct strains of Histoplasma differ in their relative virulence in mammalian hosts and in production of and requirement for specific virulence factors. The close similarity in the genome sequences of these diverse strains suggests that phenotypic variations result from differences in gene expression rather than gene content. To provide insight into how the transcriptional program translates into morphological variation and the pathogenic lifestyle, we compared the transcriptional profile of the pathogenic yeast phase and the non-pathogenic mycelial phase of two clinical isolates of Histoplasma.To overcome inaccuracies in ab initio genome annotation of the Histoplasma genome, we used RNA-seq methodology to generate gene structure models based on experimental evidence. Quantitative analyses of the sequencing reads revealed 6% to 9% of genes are differentially regulated between the two phases. RNA-seq-based mRNA quantitation was strongly correlated with gene expression levels determined by quantitative RT-PCR. Comparison of the yeast-phase transcriptomes between strains showed 7.6% of all genes have lineage-specific expression differences including genes contributing, or potentially related, to pathogenesis. GFP-transcriptional fusions and their introduction into both strain backgrounds revealed that the difference in transcriptional activity of individual genes reflects both variations in the cis- and trans-acting factors between Histoplasma strains.Comparison of the yeast and mycelial transcriptomes highlights genes encoding virulence factors as well as those involved in protein glycosylation, alternative metabolism, lipid remodeling, and cell wall glycanases that may contribute to Histoplasma pathogenesis. These studies lay an essential foundation for understanding how gene expression variations contribute to the strain- and phase-specific virulence differences of Histoplasma.
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Project description:BackgroundProtein synthesis is a cellular process that takes place through the successive translation events within the ribosome by the event-specific protein factors, namely, initiation, elongation, release, and recycling factors. In this regard, we asked the question about how similar are those translation factors to each other from a wide variety of bacteria? Hence, we did a thorough in silico study of the translation factors from 495 bacterial sp., and 4262 amino acid sequences by theoretically measuring their pI and MW values that are two determining factors for distinguishing individual proteins in 2D gel electrophoresis in experimental procedures. Then we analyzed the output from various angles.ResultsOur study revealed the fact that it's not all same, or all random, but there are distinct orders and the pI values of translation factors are translation event specific. We found that the translation initiation factors are mainly basic, whereas, elongation and release factors that interact with the inter-subunit space of the intact 70S ribosome during translation are strictly acidic across bacterial sp. These acidic elongation factors and release factors contain higher frequencies of glutamic acids. However, among all the translation factors, the translation initiation factor 2 (IF2) and ribosome recycling factor (RRF) showed variable pI values that are linked to the order of phylogeny.ConclusionsFrom the results of our study, we conclude that among all the bacterial translation factors, elongation and release factors are more conserved in terms of their pI values in comparison to initiation and recycling factors. Acidic properties of these factors are independent of habitat, nature, and phylogeny of the bacterial species. Furthermore, irrespective of the different shapes, sizes, and functions of the elongation and release factors, possession of the strictly acidic pI values of these translation factors all over the domain Bacteria indicates that the acidic nature of these factors is a necessary criterion, perhaps to interact into the partially enclosed rRNA rich inter-subunit space of the translating 70S ribosome.
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Project description:Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes.
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