Year: 2020
Type: dissertation
Abstract: Glioblastoma (GBM) is the most aggressive primary brain tumour of adults. Targeting the self-renewal property of glioblastoma stem cells (GSCs) is critical for tumour eradication. Our lab found that patient-derived GSCs with high expression of ASCL1 (ASCL1hi) were competent to undergo neuronal differentiation in response to differentiation cues and this was associated with reduced tumorigenicity. Overexpressing ASCL1 in the initially unresponsive subset, ASCL1lo GSCs, was able to enforce a neuronal cell fate. The epigenetic mechanisms underlying differentiation of GSCs have not been fully elucidated. In this thesis, I uncover distinct accessible chromatin landscapes, where ASCL1hi GSCs are primed for neuronal differentiation, while ASCL1lo GSCs are enriched for immune pathways. I further provide functional evidence for a potential upstream transcriptional regulator of ASCL1. Finally, I reveal changes in histone post-translational modifications that may contribute to ASCL1-mediated differentiation of GSCs. These results provide early insights into the epigenetic requirements of differentiation therapy for GBM.
Source: TSpace (University of Toronto)
Author: Julia E. Jaramillo
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3144993117