Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

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7.1 Enrichment Analysis Results proteins outside the cellular membrane, MHC class I receptors can cause the activation of cytotoxic T cells against exogenous peptides derived from an in- fection. In fact, healthy cells are ignored by the cytotoxic T cells thanks to the sensitivity of the recognition system between the loaded MHC class I receptor and the T cell receptor, while cells containing foreign proteins can be recog- nised and, therefore, killed. MHC class I molecules are heterodimers and they consist of two polypeptide chains, the α and the β2-microglobulin chain, of which only the α chain is polymorphic. Loading of MHC class I receptors with peptides occurs inside the lumen of the endoplasmic reticulum (ER) [323]. The exogenous pathway is used by a cohort of specialised cells termed professional Antigen Presenting Cells, or APCs. These cells are macrophages, dendritic cells and B cells and they present fragments of extracellular proteins to helper CD4 + T cells triggering a cell-mediated (Th1) or humoral (Th2) re- sponse for peptides deriving from extracellular pathogens. The receptors that are responsible for such presentation are the MHC class II molecules. MHC class II molecules, like the MHC class I molecules, are heterodimers but the MHC class II molecules consist of two homologous peptides, the α and β chain, both polymorphic and encoded by the HLA gene. Loading of both classes occurs inside the cell, but MHC class II molecules are loaded only when the vesicle generated at the ER fuses with a lysosome containing digested endo- cysed extracellular proteins. In the ER vesicle, the MHC class II molecule has its peptide-binding cleft blocked by CD74, a trimer called "invariant chain" which prevents the binding of cellular peptides. Once this vesicle fuses with the lysosome, the MHC class II molecules are unloaded with the invariant chain and reloaded with a peptide from the lysosome via an MHC class II-like structure called HLA-DM. The stable MHC class II thus formed is presented on the cell surface. the expression of MHC class II molecules is constitutive only on professional APCs but can be induced by cytokines such as IFNG on other cell types, including cancer cells [492]. All genes involved in the two pathways are listed below (7.3) [327], showing all alleles of the same Human Leukocyte Antigen (HLA) class. In a study on ovar- ian cancer, the MHC class II receptor α polymorphic chain, encoded by the HLA-DRA gene, was found to be the most over-expressed gene [421]. Although also the β chain, HLA-DRB, was over-expressed, the almost complete lack of this polypeptide at the protein level via an unknown post-transcriptional or post-translational mechanism of regulation, precluded the formation of a mature HLA-DR receptor and a similar pattern was observed when staining brain 166
7.1 Enrichment Analysis Results Table 7.3: Summary of all MHC class I and II genes and the FC (F DR > 10%) of those measured in the Tag-seq dataset. Cytosolic pathway Exogenous pathway Gene log 2(F C) Gene log 2(F C) HLA-A 3.04 Alpha chains HLA-B HLA-DMA Inf HLA-C HLA-DQA HLA-E 2.09 DPA1 5.73 HLA-F DQA1 Inf HLA-G DRA 5.68 HLA-K Beta chains HLA-L HLA-DMB B2M HLA-DOB PSMB5 HLA-DPB1 3.83 PSMB6 HLA-DQA2 6.56 PSMB7 HLA-DQB1 4.60 PSMB8 HLA-DQB2 PSMB9 HLA-DRB1 PSMB10 HLA-DRB3 TAP1 2.36 HLA-DRB4 TAP2 HLA-DRB5 8.36 CANX Invariant chains CALR CD74,CLIP 7.11 TAPBPL 2.57 Transcriptional co-activator CIITA tumour tissue [419]. It seems that compensatory mechanisms such as cyto- plasm over-expression of Ii/CD74 and reduction of HLA-DRB are in action to decrease the tumour’s immunogenicity by decreasing the ability of MHC class II to present tumour-specific antigens to the host immune system. Interest- ingly, no such mechanism is observed in our study, in which HLA-DRA, HLA- DRB and CD74 are all over-expressed in the GNS cell lines with a fold-change much greater than two (Table 7.3). The same magnitude of up-regulation is observed for the MHC class II-like peptide HLA-DM that aids in the unloading of CD74 and loading of immature MHC class II receptors with the extracellular peptides present in the lysosome to form the mature molecule. Other two MHC class II αβ heterodimer receptors are over-expressed according to our dataset and these are HLA-DP and HLA-DQ. In fact, both homologue chains encoded by the HLA-DPA1 and HLA-DPB1 loci and HLA-DQA1 and HLA-DQB1 loci are over-expressed and have the potential to form a mature MHC class II receptor. Altogether these findings suggest that in the GNS cell lines the exogenous pathway is not affected by compensatory mechanisms of 167
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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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5.5 Literature Mining Methods Figur
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5.5 Literature Mining Methods How m
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5.6 Differential Isoform Expression
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5.9 External Dataset Expression Cor
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8.5 Target Prediction Ensemble Anal
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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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