Mortimer, Thomas;
(2019)
Defining the Molecular and Cellular Mechanisms of EZH2's Dynamic Role in Tumourigenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Epigenetic regulators are recurrently hijacked by cancer cells to enhance and maintain their malignant properties. Remarkably, epigenetic regulators are often co-opted by cancer cells in their wild-type unmutated form without any discernible changes to their intrinsic properties. However, the molecular mechanisms that underlie the co-option of these key regulators of cellular identity remain largely unclear. To generate a mechanistic paradigm for this phenomenon, I investigate how the Polycomb component EZH2 transitions from its physiological role in regulating normal development and tissue maintenance, to its pathological role as a tumour promoter. Focussing on the role of EZH2 in the central nervous system, I show that oncogenic signalling redistributes EZH2 on chromatin, leading to transcriptional misregulation of key neural homeotic genes and a malignant rewiring of normal development programmes. This is achieved by de-repression of spinal cord-specifying HOX genes and repression of the forebrain and neural stem cell transcription factor EMX2, an expression switch observed in both glioblastoma cell lines and patient samples. By in vivo assays, I show that EMX2 is a potent tumour suppressor in glioblastoma, suggesting that EMX2 repression by EZH2 is important for glioblastoma maintenance. Beyond its chromatin distribution, I also show that transformation alters the binding partners of EZH2, suggesting that dynamic changes to the composition of Polycomb complexes may promote tumour formation. Thus, by performing a detailed multi-omics characterisation of how neoplastic transformation alters the distribution, activity and binding partners of EZH2, I provide a unique insight into the molecular and cellular mechanisms underlying wild-type EZH2's dynamic role in tumourigenesis.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Defining the Molecular and Cellular Mechanisms of EZH2's Dynamic Role in Tumourigenesis |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10078138 |
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