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The NRSF and USF Transcription Factor Families Regulate Pro-Convulsant Neuropeptides and Are Targets

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The NRSF and USF Transcription Factor Families Regulate Pro-Convulsant Neuropeptides and Are Targets The NRSF and USF transcription factor families regulate pro-convulsant neuropeptides and are targets for anti-convulsant drug treatment: Implications for epilepsy. Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Stuart Graham Gillies. October 2009 The NRSF and USF transcription factor families regulate pro-convulsant neuropeptides and are targets for anti-convulsant drug treatment: Implications for epilepsy. Stuart G Gillies Epilepsy is a chronic neurological disorder which can arise following an initial insult that over time, progresses into a condition characterised by recurrent spontaneous seizures. During a latent period between the initial insult and the epilepsy condition proper, major changes occur within the brain at both a cellular and molecular level, in a process known as epileptogenesis. It is postulated that during epileptogenesis, signal transduction pathways are perturbed following the initial insult, which may bring about long term changes in gene expression profiles. For example, the expression of a host of neuropeptides is known to be modulated in response to an initial insult, including the up-regulation of the pro-convulsant tachykinins Substance P and Neurokinin B, encoded by the TAC1 and TAC3 genes, respectively. In this thesis I have explored the regulation of both of these genes by two distinct transcription factor (TF) families; the Neuron Restrictive Silencing Factor (NRSF) isoforms, and the Upstream Stimulatory Factor (USF) proteins. I demonstrate that both NRSF and USF variants regulate TAC3 promoter activity, and that NRSF isoforms can modulate endogenous NKB expression in a human neuroblastoma cell line. Furthermore, these distinct TF families are shown to work in cooperation to regulate the activity of the rat TAC1 promoter. Thus, both NRSF and USF variants are shown to be important in the regulation of pro-convulsant neuropeptides and as both NRSF and USF proteins have been shown to be induced by pro-convulsant stresses here, they are potential key TFs in epileptogenesis, responding to an initial insult, and orchestrating downstream gene expression changes. Consistent with such a model, I have also revealed that both NRSF and USF variants are modulated by anti-convulsant drug treatment. Here, three distinct anti-convulsant drugs, were found to differentially modulate the expression of both the full-length NRSF, and its truncated isoform, as well as the USF proteins USF1 and USF2. Furthermore, whilst the drugs had limited impact upon the localisation of these TFs in human neuroblastoma cells, they did affect the binding of these TFs to target DNA sequences, particularly NRSF binding to its recognition DNA sequence, the NRSE, in a number of genes. In addition, due to an increasingly appreciation of the role of cocaine and the dopaminergic pathways in seizure progression, I explored the impact of cocaine treatment on the expression of these TFs. Cocaine was found to modulate both NRSF and USF variant expression, and NRSF binding to target DNA sequences. These findings suggest that both NRSF and USF variants are important in epileptogenesis and are targets for modulation by the anti-convulsant drugs investigated here. To further explore the significance of NRSF expression in seizure progression, I explored the impact of over-expression of NRSF isoforms, modelling that which occurs in response to seizure in animal models, on global gene expression pathways. I reveal that NRSF isoform over-expression significantly modulates the expression of a host of genes with known associations with epilepsy, supporting a model that NRSF isoforms are key TFs which respond to the initial insult and coordinate long-term changes in gene expression. These findings may help our understanding of the molecular mechanisms at work during epileptogenesis, and may better our understanding of the progression of epilepsy. Acknowledgements I would like to take this opportunity to thank the many people who have helped and supported me throughout my PhD. Firstly I would like to thank my supervisors Professor John Quinn and Dr Jill Bubb, for all their support, direction and friendship over the past three years, that has not only shaped my project, but also me as a person. I would also like to thank my lab colleagues in white block, most notably Dr Kate Haddley, Dr Sylvia Vasiliou and Dr Fahad Ali, who I now consider to be life-long friends. Their friendship and support helped me overcome all the barriers that a three-year PhD project presented, and for that I am extremely grateful. I would also like to thank Dr Helen Burrell, Mr Iain Kirk, Miss Hannah Stevens, Dr Moutasem Abo-onq, Dr Gregory Jacobson and Mr Steven Thompson, who have all helped me over the past three years. Finally, I would like to thank my PhD course organisers and past MRes supervisors who all helped shape me as a scientist, including Professor Andrea Varro, Dr David Criddle and Dr Sylvia Urbe. I also wish to thank the MRC for funding my PhD Studentship. On a more personal note, I am fortunate to have a fantastic family and great number of friends who have all provided support for me over the past few years, whether it was listening to my moans, or just simply helping me to relieve stress with a few pints. I would like to take this opportunity to thank my parents for 27 years love, support and encouragement. They have worked hard throughout their lives to provide a platform for me to achieve my aspirations, and for that I am eternally thankful. I would also like to thank Bob, Nicola, Ste and Joe, who have always been there for me and provided much needed love and laughter. Finally I would like to thank my fiancée Catherine, who has lived through all the good times and the bad times with me, and has supported me through both. Catherine has been both my rock and inspiration throughout my PhD and I will always love her and be thankful for all she has done for me. CONTENTS PAGE ABBREVIATIONS .............................................................................................................................................................VII CHAPTER 1: GENERAL INTRODUCTION ............................................................................................................... 10 1.1 EPILEPSY....................................................................................................................................................................... 10 1.1.1 SOCIAL CONTEXT .................................................................................................................................10 1.1.2 THE HIPPOCAMPUS AND SEIZURE..............................................................................................................2 1.1.3 MOLECULAR CHANGES ASSOCIATED WITH EPILEPTIC SEIZURE..........................................................................4 1.1.4 NEUROPEPTIDES IN EPILEPSY ...................................................................................................................6 1.1.5 EPILEPTOGENESIS ..................................................................................................................................7 1.1.6 EPIGENETICS AND EPILEPTOGENESIS ..........................................................................................................9 1.1.7 SEIZURE MODELS................................................................................................................................10 1.2 THE TACHYKININS .................................................................................................................................................... 14 1.2.1 THE TACHYKININ FAMILY ......................................................................................................................14 1.2.2 NEUROKININ B (NKB) .........................................................................................................................15 1.2.3 REGULATION OF NKB ..........................................................................................................................18 1.2.4 SUBSTANCE P (SP)..............................................................................................................................20 1.2.5 REGULATION OF TAC1.........................................................................................................................22 1.3 GENE REGULATION................................................................................................................................................... 26 1.3.1 TRANSCRIPTION ..................................................................................................................................26 1.3.2 CHROMATIN.......................................................................................................................................29 1.3.3 CHROMATIN REMODELLING...................................................................................................................30 1.3.4 HISTONE MODIFICATIONS .....................................................................................................................33 1.3.4.1 Histone acetylation.................................................................................................................34 1.3.4.2 Histone methylation ...............................................................................................................35 1.4 NEURON RESTRICTIVE SILENCER FACTOR (NRSF) .......................................................................................
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