Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

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6.8 Long ncRNA Differential Expression Results lysosomal cysteine protease that is part of the peptidase C1 family of proteins and is responsible for activating serine proteases in immune and inflammatory cells to function in processes of bone remodelling, epidermal homeostasis, and antigen presentation [500]. During cancer progression cathepsins are secreted into the extracellular matrix where they promote tumour invasion by cleav- ing components of the matrix and the basement membrane, thereby creating a passageway for the migration of cancer cells. The disruption of adherens junctions via cleavage of E-cadherin is another example. Cathepsins can also initiate proteolytic cascades in which they activate other proteases such as matrix metalloproteinases, which in turn promote invasion [166,167]. Mem- bers B, L and S of the cathepsin family have been identified as regulators of E-cadherin function through cleavage of its N-terminus. Knockout mice mutants for cathepsins B, L or S show obvious defects such as the decrease of tumour cell proliferation, tumour invasion and tumour vascularity, while CTSC - / - knockout mice have more subtle defects that consist in failing to activate granzymes A and B in cytotoxic lymphocytes [167]. The hypothetical regulation performed by the long non-coding RNA BC038205 on CTSC isoforms could be one of maintaining the expression levels of this gene high in GNS cell lines through a form of direct regulation which is re- lieved when the non-coding RNA is absent or expressed at lower levels, such as in NS cells. In figure 6.21 three panels are shown in which the location (panel a) of the CTSC isoforms and that of the non-coding RNA is shown along the human reference genome; the expression levels as detected by Tag-seq (panel b) are displayed in a histogram to visually highlight the relationship between them; a correlation plot (panel c) that shows the presence of a correlation in both the expression trends between the first CTSC isoform and the non-coding RNA BC038205, and the second CTSC isoform and the same non-coding RNA gene. The correlation was calculated with the cor.test function in the R stats package that uses the Pearson’s product moment correlation coefficient to test for association between paired samples. HOTAIRM1 is known to be strongly up-regulated in human NB4 promyelo- cytic cell lines and normal hematopoietic cells upon induction of granulocytic differentiation and is found to be up-regulated in our GNS lines as well as in the gliomas from the Parsons et al [383] Tag-seq data with respect to our fetal human NS cell lines and the Parsons et al primary brain samples. Interestingly, its knock-down in NB4 cells causes down-regulation of HOXA1 and HOXA4 genes and these genes are up-regulated in our Tag-seq dataset (Fig 6.22). 158
6.8 Long ncRNA Differential Expression Results Figure 6.21: Correlated expression of CTSC and a nearby ncRNA. (a) CTSC (cathepsin C) is located in a gene desert harboring an uncharacterized ncRNA transcribed in the opposite direction (cDNA BC038205). Image adapted from the Ensembl Genome Browser [147]. (b) Both CTSC and the ncRNA have strongly elevated expression in the GNS lines relative to the NS lines, with highest levels in G179.(c) Correlation plots for the BC038205 ncRNA and first isoform of CTSC (grey) and second isoform of CTSC (blue). 159
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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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Chapter 4 The Non-Coding RNA World
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4.1 MicroRNA regulation Introductio
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4.1 MicroRNA regulation Introductio
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4.2 Target Prediction and Validatio
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Methods 93
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5.1 Tag-sequencing Data Processing
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5.1 Tag-sequencing Data Processing
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5.2 Array Comparative Genomic Hybri
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5.4 Quantitative Real Time-PCR Vali
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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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Bibliography [1] Cell signaling tec
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