Al-Jabri, Muna Mubarak Hamed (2023) Investigating the role of JARID2 in treatment resistance in glioblastoma. PhD thesis, University of Leeds.
Abstract
Glioblastoma (GBM) is the deadliest primary brain tumour in adults with a median survival of 14-20 months from initial diagnosis. Despite aggressive treatment involving maximal surgical debulking followed by radiation therapy and chemotherapy, GBM remains incurable owing to a high rate of fatal recurrence. Understanding why unresected tumour cells survive treatment is necessary to better treat this disease. GBM tumours recur due to the presence of treatment-resistant cells, and this resistance phenotype is posited to be mediated by several epigenetic mechanisms including DNA methylation, histone modifications and chromatin remodelling. Work within the Glioma Genomics group in Leeds has specifically highlighted a potential role for histones, so this study focuses on understanding the role of histone modifications in GBM treatment resistance. More specifically, this group has recently proposed, for the first time, that Jumonji and AT- Rich Interacting Domain 2 (JARID2) plays a role in tumour recurrence via chromatin remodelling in GBM. JARID2 is an accessory protein of Polycomb Repressive Complex 2 (PRC2) which is the sole complex responsible for trimethylation on lysine 27 of histone H3 (H3K27me3). JARID2 promotes PRC2 recruitment to chromatin and regulates its enzymatic activity. PRC2 and JARID2 have a fundamental role in neurodevelopment but the role in GBM treatment resistance needs to be investigated. This can be achieved by generating genome-wide profiles of histone modifications associated with JARID2, and the binding of JARID2 itself, in paired primary (untreated) and recurrent (posttreatment) samples. Despite the tremendous work in generating global genome-wide profiling of histone modifications in various types of cancers, few genome-wide maps for H3K27me3 are available for GBM, therefore, current interest is placed on generating and comparing genome-wide mapping of histone modifications to locate and identify key epigenetic changes that are associated with GBM development and progression. Another histone mark (H3K4me3, which is a transcriptional activator) is known to work in concert with H3K27me3 during cell lineage determination in the brain, so it was also deemed necessary to prolife this mark. Thus, this study aimed to establish a workflow for generating and comparing the global distribution patterns of two histone modifications, along with binding patterns of the catalytic component of PRC2 (Enhancer of zeste homolog 2: EZH2) and JARID2, in paired primary and recurrent GBM samples. My hypothesis is that histone remodeling is driving the changes in the gene expression observed in GBM through treatment. I established iv a workflow and then generated a genome- wide chromatin landscape for H3K27me3, H3K4me3 and EZH2 binding from matched fresh frozen pair primary and recurrent GBM samples of our in-house dataset. Then, I performed an integrative analysis on histone marks along with EZH2 by correlating their modifications with the changes in gene expression. The analysis was performed on a subset of genes that have been found to be dysregulated in GBM’s patient following standard treatment due to the epigenetic remodeling of their promoters. The findings revealed that these genes are significantly found in the bivalent state, but the balance of histone marks is altered by therapy. Also, it revealed that histone modifications are driving gene expression in those genes more than the others This leads to the hypothesis that this bivalency is what causes the tumours to be able to adapt to treatment. I concluded that JARID2 genes facilitate tumour recurrence through transcriptional reprogramming in patients following standard therapy. Additionally, it implies that bivalent areas promote GBM tumorigenicity and are linked to chemo-resistance.
Metadata
Supervisors: | Stead, Lucy and Hughues, Thomas and Matthews, Laura |
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Keywords: | Glioblastoma, TMZ, JARID2, Chromatin remodeling, Histone modification, Transcriptional reprograming, Methylation |
Awarding institution: | University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Depositing User: | Mrs Muna Mubarak Hamed Al-Jabri |
Date Deposited: | 05 Mar 2024 12:41 |
Last Modified: | 05 Mar 2024 12:41 |
Open Archives Initiative ID (OAI ID): | oai:etheses.whiterose.ac.uk:33978 |
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