Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

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6.4 Core Differentially Expressed Genes Results several cancers. LMO4 is well-characterised as an oncogene in breast cancer, but has not been studied in glioma. LMO4 is regulated trough the PI3K pathway, which is known to be affected in glioma [?,340]. · The transcription factor gene CEBPB is a well-characterised glioma oncogene, recently suggested to be a master regulator of a mesenchy- mal gene expression signature associated with poor prognosis [85]. · CD9 is a membrane protein implicated in invasion [253] and regulation of EGF receptor activation [455]. Its expression in astrocytic tumours correlates with malignancy [220]. · MT2A encodes a metallothionein found to suppress apoptosis in cancer cell lines [110], potentially by causing TP53 to misfold [411]. Inversely correlated expression of MT2A and TP53 proteins have been observed in glioblastoma specimens [306]. · NTRK2 encodes a receptor for brain-derived neurotrophic factor, pro- moting differentiation, proliferation and survival [118]. In several tumour types, its expression correlates with poor prognosis and metastasis [118] and the protein has been detected in a subset of cells in astrocytomas [29]. As shown in figure 6.11 the Tag-seq data available for NTRK2 happens to identify a long and a shorter isoform for this gene, potentially the one lacking the kinase domain that has also been implicated in the regulation of astrocyte morphology [366]. · FOXG1, a transcription factor gene involved in brain development, is commonly amplified in the childhood brain tumour medulloblastoma [9]. FOXG1 has been proposed to act as an oncogene in glioblastoma as well, by suppressing growth-inhibitory effects of TGFβ [448]. The set of core up-regulated genes also includes multiple genes suggested to play a role in other neoplasias, but for which we failed to find any studies implicating them in glioma. For five of these, previous studies have pointed to a role in motility and invasion: PLS3 [26,163], LMO4 [475], BACE2 [243,499], CTSC [113,530,551] and MMP17 [88,430]. Further examples of genes implicated in other cancers include the putative growth factor EPDR1 [8,360], which is highly expressed in some progenitor cell types [178], and PMEPA1, which can act as an oncogene by affecting the PI3K pathway and PTEN stability [460]. A subset of the core up-regulated genes have to the best of our knowledge 134
6.4 Core Differentially Expressed Genes Results Figure 6.11: NTRK2 is a brain-derived neurotrophic factor detected in the literature in a subset of cells in astrocytomas [29] and found in our Tag-seq dataset by mappings of tags on the shortest isoform. Three tracks are visible in the figure: at the top, a customised track composed of 12 sub-tracks representing the expression levels of our GNS cell lines and NS cell lines in red - for tag mappings on the minus strand - and blue - for tag mappings on the plus strand. The level of tag expression is indicated by the thickness of the line representing the mapped tag; at the centre a track representing UCSC genes, RefSeq genes and Ensembl genes; at the bottom a track showing the zoom in of the central track region where the tag mapping takes place. The thicker lines in the bottom track indicate the 3’UTRs of the gene. The tags representing the NTRK2 gene map onto a region that identifies both the shorter - potentially the one that lacks the kinase domain - and a longer isoform. Adapted from the UCSC genome browser (our Tag-seq track for hg19 is added by pasting the following line into the custom track box http://gns: zed9epre@www.ebi.ac.uk/\~engstrom/gns/tracks/hg19/gns\_tpm.bg.gz). 135
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Transcriptional Characterization of
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This dissertation is my own work an
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Acknowledgements I would like to th
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5.9 External Dataset Expression Cor
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Introduction 1
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1.1 Glial Cells in the Central Nerv
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1.2 Glioblastoma Multiforme Introdu
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1.3 Primary and Secondary Glioblast
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1.4 Pathways Involved in Glioblasto
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1.5 Pathway Crosstalk Introduction
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Chapter 2 Neurogenesis Contents 2.1
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2.1 Radial Glia Introduction VZ adj
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2.2 Neural Stem Cells Introduction
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Chapter 3 Brain Cancer Stem Cells C
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3.1 The Cancer Stem Cell Hypothesis
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3.1 The Cancer Stem Cell Hypothesis
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3.2 Brain Cancer Stem Cells Introdu
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3.3 Glioma Culture Systems Introduc
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7.4 Survival Analysis Results 867 g
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7.5 Glioblastoma Pathway Analysis R
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8.1 Principles Results say, this is
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8.3 Databases Results Figure 8.1: O
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8.3 Databases Results Figure 8.3: W
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8.4 Filters Results Bayesian method
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8.5 Target Prediction Ensemble Anal
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9.1. Digital Profiling of GNS Cell
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9.2. MicroRNA Target Prediction Ana
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9.3. Concluding Remarks Appendix pr
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A.1 Differential Expression Appendi
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A.2 Classified Differential Express
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A.3 Quantitative RT-PCR Appendix Ta
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A.3 Quantitative RT-PCR Appendix We
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A.3 Quantitative RT-PCR Appendix Ta
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A.3 Quantitative RT-PCR Appendix We
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A.4 Tag-seq vs qRT-PCR Correlation
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Appendix "BEX5", "DIAPH2", "GBP3",
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End Select End If End Sub Appendix
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If NameStr.ToLower().Equals("query"
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Appendix C Long ncRNAs We detected
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C. Long ncRNAs Appendix Tag Accessi
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D.1 Pathway Interactions Appendix F
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D.2 Pathway Images Appendix Figure
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D.2 Pathway Images Appendix Figure
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E. Exon Array Data Appendix Average
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F. MicroRNA Array Data Appendix Tab
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F. MicroRNA Array Data Appendix GNS
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F. MicroRNA Array Data Appendix GNS
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Ln Natural logarithm LOH Loss of He
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3.3 Schematisation of cell cycle ph
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8.3 Workflows at the core of the pr
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7.1 Selected Gene Ontology terms an
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