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Title: Investigating the mechanism of FOXG1 in glioblastoma stem cells
Author: Ferguson, Kirsty Megan
ISNI:       0000 0004 8510 4860
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2020
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Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer in adults. Relapse after conventional surgery and chemo/radiotherapy is thought to be driven by glioblastoma stem cells (GSCs). GSCs have phenotypic sumularities to normal neural stem cells (NSCs) and frequently overexpress many key neurodevelopmental transcription factors, including FOXG1, a key forebrain transcription factor with reporgramming activity. Evidence points to an important funtional role of FOXG1 in driving the NSC-like identity of GSCs. Here we explore the mechanisms by which FOXG1 acts, by characterising its key downstream transcritional targets and protein-protein interactions. Analysis of the transcriptional changes induced by FOXG1 overexpression identified key targets, including cell cycle and epigenetic regulators, such as Fox06 and Chd3. Fox06 was identified as a clear downstream target with a functional role in enabling FOXG1 to drive exit from quiescence. This also revealed the FOXG1, a transcriptional repressor, can lead to gene activation. The H3K4 demethylase JARID1B (KDM5B/PLU-1), a negative regulator of promoter activation, is thought to be a protein partner of FOXG1. We hypothesised that FOXG1 may activate gene expression by sequestration of this repressor. However, our studies suggest JARID1B is not essential for FOXG1's ability to drive a proliferative NS cell-like state, nor transcriptional activiation of Fox06 or Chd3. FOXG1 immunoprecipitation studies highlighted difficulties in obtaining good quality, protein-specific antibodies for characterising protein partners. we therefore exploited CRISPR/Cas9 technology to epitope-tag endogenous FOXG1 in patient-derived glioblastoma NS (GNS) cells. These cellular models can now be used in future studies to define FOXG1's key protein partners and aid the identification of ways to therapeutically target FOXG1 in GBM.
Supervisor: Pollard, Steven ; Soufi, Abdenour Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: glioblastoma ; glioblastoma stem cells ; transcription factor ; FOXG1 ; CRISPR-Cas9