Interrogating the Epigenetic Determinants of State Heterogeneity in Adult Glioblastoma

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dc.contributor.advisorGallo, Marco
dc.contributor.authorNikolic, Ana
dc.contributor.committeememberChan, Jennifer
dc.contributor.committeememberWeiss, Samuel
dc.contributor.committeememberGoodarzi, Aaron
dc.contributor.committeememberHawkins, Cynthia
dc.date2023-02
dc.date.accessioned2023-01-31T18:45:10Z
dc.date.available2023-01-31T18:45:10Z
dc.date.issued2023-01-24
dc.description.abstractGlioblastoma is the most common malignant brain tumour in adults, and prognosis remains poor, with most patients dying in a year or two despite aggressive treatment. These tumours have high degrees of intratumoral heterogeneity, with a subpopulation of cells having stem cell properties. The drivers of this stem cell phenotype are complex, and include a large number of epigenetic and genetic factors. In this thesis, I explore glioblastoma heterogeneity in two distinct ways: I use single-cell chromatin accessibility data to explore influences of copy number alterations on the glioblastoma epigenome, and I apply functional experimental techniques and genomics to characterize macroH2A2, an epigenetic regulator in this disease. In the first part of my thesis, I develop a tool for calling copy number alterations in single-cell ATAC-seq data, called CopyscAT, and show that glioblastoma tumours have limited intratumoral genetic heterogeneity. In addition, genetic subclones share similar epigenetic profiles, but with slightly different predispositions to acquiring distinct cellular states. In the second section of the thesis, I focus on the role of macroH2A2, a histone variant involved in development and cancer. I find that expression of macroH2A2 is associated with improved prognosis in glioblastoma patients, especially in patients receiving treatment. Examining existing datasets, I find that macroH2A2 expression is enriched in neural progenitor-like cells and repressed at the leading edge of tumours, and confirm this in primary patient specimens. MacroH2A2 is associated with reduced self-renewal in vitro and in vivo and knockdown of the protein increases self-renewal markers, reduces the proportion of CD44-positive cells, and shortens mouse survival. Genome-wide, macroH2A2 knockdown results in altered accessibility, with loss of early response (FOS/AP-1) motifs, which I confirm in patient-derived single-cell ATAC-seq data. Chromatin immunoprecipitation confirms that direct effects of macroH2A2 are largely repressive in nature. Lastly, a screen of epigenetic drugs identifies a compound, MI-3, capable of increasing macroH2A2 levels, and shows that macroH2A2 repression impairs sensitivity to this compound. This work contributes novel ideas to the regulation of cell states and fates in glioblastoma.en_US
dc.identifier.citationNikolic, A. (2023). Interrogating the epigenetic determinants of state heterogeneity in adult glioblastoma (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.urihttp://hdl.handle.net/1880/115791
dc.identifier.urihttps://dx.doi.org/10.11575/PRISM/40696
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectepigeneticsen_US
dc.subjectglioblastomaen_US
dc.subjectcanceren_US
dc.subjectcancer biologyen_US
dc.subjectgliomaen_US
dc.subjectGBMen_US
dc.subjectmacroH2Aen_US
dc.subject.classificationBioinformaticsen_US
dc.subject.classificationNeuroscienceen_US
dc.subject.classificationMedicine and Surgeryen_US
dc.subject.classificationPathologyen_US
dc.subject.classificationBiochemistryen_US
dc.titleInterrogating the Epigenetic Determinants of State Heterogeneity in Adult Glioblastomaen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biologyen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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