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Discretization of expression Quantitative Trait Loci in Association Analysis Between Genotypes and expression Data

CURRENT BIOINFORMATICS 2015年第2期10卷 144-164页

作者： Masegosa, Andres R. Armananzas, Ruben Abad-Grau, Maira M. Potenciano, Victor Moral, Serafin Larranaga, Pedro Bielza, Concha Matesanz, Fuencisla Univ Granada CITIC Granada Spain George Mason Univ Krasnow Inst Adv Study Fairfax VA 22030 USA Poten Dynam Granada Spain Univ Politecn Madrid Computat Intelligence Grp Dept Inteligencia Artificial Madrid Spain CSIC Inst Parasitol Lopez Neyra Granada Spain

expression quantitative trait loci are used as a tool to identify genetic causes of natural variation in gene expression. Only in a few cases the expression of a gene is controlled by a variant on a single genetic marker. There is a plethora of different complexity levels of interaction effects within markers, within genes and between marker and genes. This complexity challenges biostatisticians and bioinformatitians every day and makes findings difficult to appear. As a way to simplify analysis and better control confounders, we tried a new approach for association analysis between genotypes and expression data. We pursued to understand whether discretization of expression data can be useful in genome-transcriptome association analyses. By discretizing the dependent variable, algorithms for learning classifiers from data as well as performing block selection were used to help understanding the relationship between the expression of a gene and genetic markers. We present the results of using this approach to detect new possible causes of expression variation of DRB5, a gene playing an important role within the immune system. Together with expression of gene DRB5 obtained from the classical microarray technology, we have also measured DRB5 expression by using the more recent next-generation sequencing technology.

关键词： eQTL gene expression microarray machine learning RNA-seq SNP

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Bioinformatics with soft computing

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IEEE TRANSACTIONS ON SYSTEMS MAN AND CYBERNETICS PART C-APPLICATIONS AND REVIEWS 2006年第5期36卷 616-635页

作者： Mitra, Sushmita Hayashi, Yoichi Meiji Univ Dept Comp Sci Kawasaki Kanagawa 2148571 Japan

Soft computing is gradually opening up several possibilities in bioinformatics, especially by generating low-cost, low-precision (approximate), good solutions. In this paper, we survey the role of different soft computing paradigms, like fuzzy sets (FSs), artificial neural networks (ANNs), evolutionary computation, rough sets (RSes), and support vector machines (SVMs), in this direction. The major pattern-recognition and data-mining tasks considered here are clustering, classification, feature selection, and rule generation. Genomic sequence, protein structure, gene expression microarrays, and gene regulatory networks are some of the application areas described. Since the work entails processing huge amounts of incomplete or ambiguous biological data, we can utilize the learning ability of neural networks for adapting, uncertainty handling capacity of FSs and RSes for modeling ambiguity, searching potential of genetic algorithms for efficiently traversing large search spaces, and the generalization capability of SVMs for minimizing, errors.

关键词： artificial neural networks (ANNs) biological data mining fuzzy sets (FSs) gene expression microarray genetic algorithms (GAs) proteins rough sets (RSes) support vector machines (SVMs)

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Molecular Elucidation of Biological Response to Mesoporous Silica Nanoparticles in Vitro and in Vivo

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ACS APPLIED MATERIALS & INTERFACES 2017年第27期9卷 22235-22251页

作者： Chou, Cheng-Chung Chen, Wei Hung, Yann Mou, Chung-Yuan Natl Chung Cheng Univ Dept Life Sci Chiayi 62102 Taiwan Natl Chung Cheng Univ Inst Mol Biol Chiayi 62102 Taiwan Natl Taiwan Univ Dept Chem Taipei 10617 Taiwan

Biomedical applications of mesoporous silica nanoparticles (MSNs) require efficient cellular uptake and low toxicity. The purpose of this study is to investigate the cellular uptake and toxicity of MSNs with different sizes and charges (50, 100, and 250 nm with a positive surface charge and 100 nm with a negative surface charge) exposed to human monocyte-derived macrophages, lung epithelium BEAS-2B cells, and mice using genome-wide gene expression analysis and cellular/animal-level end point tests. We found that MSNs can be taken up into cells through endocytosis in a charge- and size-dependent manner, with positively charged and larger MSNs being more easily taken up into the cells by recruiting more types of endocytotic pathways for more cellular uptake. Moreover, the cytotoxicity of MSNs could be correlated with the amount of MSNs taken up by cells, which positively correlates to the particle size and dosage. Therefore, only positively charged and larger MSNs (>= 100 nm) during higher treatment doses (>= 500 mu g mL(-1)) resulted in a sufficient accumulation of internalized MSNs in cells to induce significant release of reactive oxygen species (ROS) and oxidative stress, inflammatory gene upregulation through NF-kappa B and AP-1, and eventually autophagy-mediated necrotic cell death. Furthermore, genome-wide gene expression analysis could reflect the above in vitro cellular damages and corresponding in vivo injuries in mice, indicating that specific gene expression footprints may be used for assessing the safety of nanoparticles. The present finding provides some insights into the rational design of effective MSN-based drug/gene delivery systems and biomedical applications.

关键词： mesoporous silica,nanoparticles toxicity endocytosis gene expression microarray reactive oxygen species (ROS) oxidative stress inflammation autophagy

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Meta-analysis and meta-regression of transcriptomic responses to water stress in Arabidopsis

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PLANT JOURNAL 2016年第4期85卷 548-560页

作者： Rest, Joshua S. Wilkins, Olivia Yuan, Wei Purugganan, Michael D. Gurevitch, Jessica SUNY Stony Brook Dept Ecol & Evolut 650 Life Sci Stony Brook NY 11794 USA NYU Ctr Genom & Syst Biol 12 Waverly Pl New York NY 10003 USA

The large amounts of transcriptome data available for Arabidopsis thaliana make a compelling case for the need to generalize results across studies and extract the most robust and meaningful information possible from them. The results of various studies seeking to identify water stress-responsive genes only partially overlap. The aim of this work was to combine transcriptomic studies in a systematic way that identifies commonalities in response, taking into account variation among studies due to batch effects as well as sampling variation, while also identifying the effect of study-specific variables, such as the method of applying water stress, and the part of the plant the mRNA was extracted from. We used meta-analysis, the quantitative synthesis of independent research results, to summarize expression responses to water stress across studies, and meta-regression to model the contribution of covariates that may affect gene expression. We found that some genes with small but consistent differential responses become evident only when results are synthesized across experiments, and are missed in individual studies. We also identified genes with expression responses that are attributable to use of different plant parts and alternative methods for inducing water stress. Our results indicate that meta-analysis and meta-regression provide a powerful approach for identifying a robust gene set that is less sensitive to idiosyncratic results and for quantifying study characteristics that result in contrasting gene expression responses across studies. Combining meta-analysis with individual analyses may contribute to a richer understanding of the biology of water stress responses, and may prove valuable in other gene expression studies.

关键词： Arabidopsis thaliana drought response water stress meta-analysis research synthesis gene expression microarray transcriptomics

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Rac3 regulates cell proliferation through cell cycle pathway and predicts prognosis in lung adenocarcinoma

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TUMOR BIOLOGY 2016年第9期37卷 12597-12607页

作者： Wang, Gebang Wang, Huan Zhang, Chenlei Liu, Tieqin Li, Qingchang Lin, Xuyong Xie, Jingwei Liu, Hongxu China Med Univ Dept Thorac Surg Hosp 1 155 Nanjingbei St Shenyang 110001 Liaoning Peoples R China China Med Univ Dept Pathol Hosp 1 155 Nanjingbei St Shenyang 110001 Liaoning Peoples R China China Med Univ Dept Pathophysiol Coll Basic Med Sci 77 Puhe Rd Shenyang 110122 Liaoning Peoples R China Capital Med Univ Beijing Tiantan Hosp Dept Thorac Surg 6 Tiantan Xili Beijing 100050 Peoples R China

Lung cancer is still the leading cause of malignant deaths in the world. It is of great importance to find novel functional genes for the tumorigenesis of lung cancer. We demonstrated that Rac3 could promote cell proliferation and inhibit apoptosis in lung adenocarcinoma cell line A549 previously. The aim of this study was to investigate the function and mechanism of Rac3 in lung adenocarcinoma cell lines. Immunohistochemistry staining was performed in 107 lung adenocarcinoma tissues and matched non-tumor tissues. Multivariate analysis and Kaplan-Meier analysis were used to investigate the correlation between Rac3 expression and the clinical outcomes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry analysis were employed to determine the proliferative ability, cell cycle distribution, and apoptosis in H1299 and H1975 cell lines. gene expression microarray and pathway analysis between the Rac3-siRNA group and the control group in A549 cells were performed to investigate the pathways and mechanism of Rac3 regulation. Rac3 was shown to be positively expressed in lung adenocarcinoma tissues, and the expression of Rac3 associates with longer survival in lung adenocarcinoma patients. Silencing of Rac3 significantly induced cell growth inhibition, colony formation decrease, cell cycle arrest, and apoptosis of lung adenocarcinoma cell lines, which accompanied by obvious downregulation of CCND1, MYC, and TFDP1 of cell cycle pathway involving in the tumorigenesis of lung adenocarcinoma based on the gene expression microarray. In conclusion, these findings suggest that Rac3 has the potential of being a therapeutic target for lung adenocarcinoma.

关键词： Rac3 Lung adenocarcinoma Proliferation Apoptosis RNAi gene expression microarray

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The histone deacetylase inhibitor LBH589 inhibits expression of mitotic genes causing G2/M arrest and cell death in head and neck squamous cell carcinoma cell lines

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JOURNAL OF PATHOLOGY 2009年第4期218卷 467-477页

作者： Prystowsky, Michael B. Adomako, Alfred Smith, Richard V. Kawachi, Nicole McKimpson, Wendy Atadja, Peter Chen, Quan Schlecht, Nicolas F. Parish, Joanna L. Childs, Geoffrey Belbin, Thomas J. Albert Einstein Coll Med Dept Pathol Bronx NY 10461 USA Montefiore Med Ctr Bronx NY 10461 USA Albert Einstein Coll Med Dept Otorhinolaryngol Head & Neck Surg Bronx NY 10467 USA Montefiore Med Ctr Bronx NY 10467 USA Novartis Pharmaceut Cambridge MA USA Albert Einstein Coll Med Dept Epidemiol & Populat Hlth Bronx NY 10461 USA Albert Einstein Coll Med Dept Med Bronx NY 10461 USA Univ St Andrews Bute Med Sch St Andrews KY16 9TS Fife Scotland

Head and neck squamous cell carcinoma represents a complex set of neoplasms arising in diverse anatomical locations. The site and stage of the cancer determine whether patients will be treated with single or multi-modality therapy. The HDAC inhibitor LBH589 is effective in treating some haematological neoplasms and shows promise for certain epithelial neoplasms. As with other human cancer cell lines, LBH589 causes up-regulation of p21 G2/M cell cycle arrest, and cell death of human HNSCC cell lines, as measured using flow cytometry and cDNA microarrays. Global RNA expression studies following treatment of the HNSCC cell line FaDu with LBH589 reveal down-regulation of genes required for chromosome congression and segregation (SMC2L1), sister chromatid cohesion (DDX11), and kinetochore structure (CENP-A, CENP-F, and CENP-M);these LBH589-induced changes ill gene expression coupled with the down-regulation of MYC and BIRC5 (survivin) provide a plausible explanation for the early mitotic arrest and cell death observed. When LBH589-induced changes in gene expression were compared with gene expression profiles of 41 primary HNSCC samples, man.), of the genes that were down-regulated by LBH589 showed increased expression in primary HNSCC suggesting that some patients with HNSCC may respond to treatment with LBH589. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

关键词： head and neck squamous cell carcinoma histone deacetylase inhibitor gene expression microarray cell cycle arrest cell death

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An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma

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JOURNAL OF PATHOLOGY 2012年第3期228卷 274-285页

作者： Nelson, Andrew C. Pillay, Nischalan Henderson, Stephen Presneau, Nadege Tirabosco, Roberto Halai, Dina Berisha, Fitim Flicek, Paul Stemple, Derek L. Stern, Claudio D. Wardle, Fiona C. Flanagan, Adrienne M. UCL Inst Canc London WC1E 6BT England Kings Coll London Randall Div Cell & Mol Biophys London SE1 1UL England Royal Natl Orthopaed Hosp Stanmore HA7 4LP Middx England European Bioinformat Inst Cambridge CB10 1SD England Wellcome Trust Sanger Inst Cambridge CB10 1SA England UCL Dept Cell & Dev Biol London WC1E 6BT England

Chordoma is a rare malignant tumour of bone, the molecular marker of which is the expression of the transcription factor, brachyury. Having recently demonstrated that silencing brachyury induces growth arrest in a chordoma cell line, we now seek to identify its downstream target genes. Here we use an integrated functional genomics approach involving shRNA-mediated brachyury knockdown, gene expression microarray, ChIP-seq experiments, and bioinformatics analysis to achieve this goal. We confirm that the T-box binding motif of human brachyury is identical to that found in mouse, Xenopus, and zebrafish development, and that brachyury acts primarily as an activator of transcription. Using human chordoma samples for validation purposes, we show that brachyury binds 99 direct targets and indirectly influences the expression of 64 other genes, thereby acting as a master regulator of an elaborate oncogenic transcriptional network encompassing diverse signalling pathways including components of the cell cycle, and extracellular matrix components. Given the wide repertoire of its active binding and the relative specific localization of brachyury to the tumour cells, we propose that an RNA interference-based gene therapy approach is a plausible therapeutic avenue worthy of investigation. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

关键词： chordoma brachyury T sarcoma bone tumour genetics ChIP-seq gene expression microarray siRNA

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Genome-wide transcriptomic profiling of microdissected human breast tissue reveals differential expression of KIT (c-Kit, CD117) and oestrogen receptor-α (ERα) in response to therapeutic radiation

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JOURNAL OF PATHOLOGY 2009年第1期219卷 131-140页

作者： Westbury, Charlotte B. Reis-Filho, Jorge S. Dexter, Tim Mahler-Araujo, Betania Fenwick, Kerry Iravani, Marjan Grigoriadis, Anita Parry, Suzanne Robertson, David Mackay, Alan Ashworth, Alan Yarnold, John R. Isacke, Clare M. Royal Marsden NHS Fdn Trust Dept Radiotherapy Sutton SM2 5PT Surrey England Inst Canc Res Sutton SM2 5PT Surrey England Inst Canc Res Breakthrough Breast Canc Res Ctr London SW3 6JB England

The pathogenesis of late normal tissue fibrosis after high-dose ionizing radiation involves multiple cell types and signalling pathways but is not well understood. To identify the molecular changes occurring after radiotherapy, paired normal tissue samples were collected from the non-irradiated breast and from the treated breast of women who had undergone curative radiotherapy for early breast cancer months or years previously. As radiation may induce distinct transcriptional changes in the different components of the breast, laser capture microdissection and gene expression microarray profiling were performed separately for epithelial and stromal components and selected genes were validated using immunohistochemistry. In the epithelial compartment, a reduction of KIT (c-Kit;CD117) and a reciprocal increase in ESR1 (oestrogen receptor-alpha, ER alpha) mRNA and protein levels were seen in irradiated compared to non-irradiated samples. In the stromal compartment, extracellular matrix genes including FN1 (fibronectin 1) and CTGF (connective tissue growth factor;CCN2) were increased. Further investigation revealed that c-Kit and ERa were expressed in distinct subpopulations of luminal epithelial cells. Interlobular c-Kit-positive mast cells were also increased in irradiated cases not showing features of post-radiation atrophy. Pathway analysis revealed 'cancer, reproductive system disease and tumour morphology' as the most significantly enriched network in the epithelial compartment, whereas in the stromal component, a significant enrichment for 'connective tissue disorders, dermatological diseases and conditions, genetic disorder' and 'cancer, tumour morphology, infection mechanism' networks was observed. These data identify previously unreported changes in the epithelial compartment and show altered expression of genes implicated in late normal tissue injury in the stromal compartment of normal breast tissue. The findings are relevant to both fibrosis and atrophy occu

关键词： breast radiation fibrosis c-Kit oestrogen receptor mast cell stem cell factor laser capture microdissection gene expression microarray pathway analysis

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microarray analysis of bone morphogenetic protein, transforming growth factor β, and activin early response genes during osteoblastic cell differentiation

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JOURNAL OF BONE AND MINERAL RESEARCH 2002年第12期17卷 2119-2129页

作者： De Jong, DS Van Zoelen, EJJ Bauerschmidt, S Olijve, W Steegenga, WT Univ Nijmegen Dept Appl Biol NL-6525 ED Nijmegen Netherlands Univ Nijmegen Dept Cell Biol Nijmegen Netherlands NV Organon Target Discovery Unit Oss Netherlands

Bone morphogenetic protein (BMP) 2, a member of the transforming growth factor (TGF) beta family, is a potent regulator of osteoblast differentiation. In addition, both TGF-beta and activin A can either induce bone formation or inhibit bone formation depending on cell type and differentiation status. Although much is known about the receptors and intracellular second messengers involved in the action of TGF-beta family members, little is known about how selectivity in the biological response of individual family members is controlled. In this study, we have investigated selective gene induction by BMP-2, TGF-beta1 and activin A in relation to their ability to control differentiation of mouse mesenchymal precursor cells C2C12 into osteoblastic cells. TGF-beta1 can inhibit BMP-2-induced differentiation of these cells, whereas activin A was found to be without morphogenetic effect. Using a gene expression microarray approach covering 8636 sequences, we have identified a total of 57 established genes and expressed sequence tags (ESTs) that were either up-regulated or down-regulated 2 h after treatment with at least one of these three stimuli. With respect to the established genes, 15 new target genes for TGF-beta family members thus were identified. Furthermore, a set of transcripts was identified, which was oppositely regulated by TGF-beta1 and BMP-2. Based on the inverse biological effects of TGF-beta1 and BMP-2 on C2C12 cells, these genes are important candidates for controlling the process of growth factor-induced osteoblast differentiation.

关键词： bone morphogenetic protein 2 transforming growth factor beta 1 osteoblasts gene expression microarray differentiation

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Genome-wide profiling identifies elpithelial cell genes associated with asthma and with treatment response to corticosteroids

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2007年第40期104卷 15858-15863页

作者： Woodruff, Prescott G. Boushey, Homer A. Dolganov, Gregory M. Barker, Chris S. Yang, Yee Hwa Donnelly, Samantha Ellwanger, Almut Sidhu, Sukhvinder S. Dao-Pick, Trang P. Pantoja, Carlos Erle, David J. Yamamoto, Keith R. Fahy, John V. Univ Calif San Francisco Div Pulm & Crit Care Med San Francisco CA 94143 USA Univ Calif San Francisco Lung Biol Ctr Dept Med San Francisco CA 94143 USA Univ Calif San Francisco Cardiovasc Res Inst San Francisco CA 94143 USA Univ Calif San Francisco Dept Cellular & Mol Pharmacol San Francisco CA 94143 USA J David Gladstone Inst San Francisco CA 94158 USA Stanford Univ Dept Med Stanford CA 94305 USA Univ Sydney Sch Math & Stat Sydney NSW 2006 Australia

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelia[ cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.

关键词： gene expression microarray serpinB2 CLCA1 FKBP51

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