Medicine & Health

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  • (2020) Masand, Natasha
    DNA cytosine methylation is an important epigenetic modification that plays a key role in gene expression. DNA methylation has been shown to be involved in numerous processes, including X-chromosome inactivation in mammals, retrotransposon silencing, genomic imprinting, carcinogenesis and the regulation of tissue specific gene expression during development. Gene expression is tightly regulated via DNA methylation (5mC) and the aberrant expression of meiotic genes in mitotic cells via CpG promoter hypomethylation has been proposed to cause cancer. Cancer/Testis Antigens (CTAs) are a group of genes that encode tumour specific antigens and are expressed in the testis, certain cancers but not in normal post-natal somatic tissues. CpG island methylation and histone modifications appear to play a role in the epigenetic regulation of CTA expression, however, very little is known about their functions in vivo. A widely studied but poorly understood question to date is the mechanisms behind aberrant CTA reactivation in cancer. Given that 5mC mediated gene repression has been found to exist in vertebrate genomes and CTAs have also been identified to be a subset of highly evolutionarily conserved genes, it is critical to understand the role of 5mC mediated CTA silencing in vertebrates. By gaining a deeper understanding into the mechanisms behind this highly conserved pattern of gene repression on a specific subset of genes, we would be able to identify methods to prevent aberrant gene expression. In this study, I analysed publicly available whole genome bisulfite sequencing (WGBS), RNA-seq and chromatin immuno-precipitation followed by massively parallel sequencing (ChIP-seq) data of developing embryonic and adult somatic tissue of 3 vertebrate species to elucidate the evolutionary epigenetic regulation of CTAs in vertebrate genomes. Integrative WGBS, RNA-seq and ChIP-seq analysis revealed that CTAs are evolutionarily conserved in zebrafish, mice and humans and mechanisms of their epigenetic regulation are also conserved. I observed that histone modifications could potentially serve as an indicator of the methylation status of CTA gene promoters and that the expression of CTAs was inversely related to gene promoter 5mC levels. I demonstrate that CTAs when over-expressed cause embryonic lethality in zebrafish and the same genes are aberrantly hypomethylated at their CpG islands in a subset of human cancers. Overall, my work shows that CTAs are epigenetically regulated in an evolutionarily conserved manner and possibly via a conserved transcription factor, ETS1, that is expressed both in embryonic and cancerous tissue.

  • (2023) Rafla, Daniel
    There are several enduring questions regarding the differentiation of clinical phenotypes of glaucoma which clinicians may derive clinical meaning directed towards patient’s management and prognostication. This thesis seeks to address the following issues relating to distinguishing clinical phenotypes of glaucoma: “Evaluating the impact of changing visual field test density on macular structure-function relationships to identify central-involving glaucoma phenotypes”; and “Identifying quantitative structural and functional clinical parameters that may distinguish between intraocular pressure (IOP) defined glaucoma phenotypes”; Two studies were undertaken to examine clinical phenotypes of glaucoma. The first study utilised systematic approach to assessing the impact of test point density in macular visual field (VF) testing on structure-function concordance for identifying centrally-involving glaucoma phenotypes. The second study used multivariate regression analysis and principal component analysis (PCA) to examine quantitative structural (using optical coherence tomography) and functional (VF) clinical data of newly-diagnosed glucoma patients to determine if there are clinically meaningful distinctions between IOP-defined phenotypes (i.e. low-tension vs high-tension glaucoma). Study 1) Using a systematic approach of test point addition and subtraction, we identified a critical number of test locations (8-14) in macular VF testing where binarised structure-function concordance is maximised, and discordance minimised. This methodology provides a framework for optimising macular VF test patterns for detection of centrally-involving glaucoma phenotypes. Study 2) Despite statistical significance in differences between low- and high-tension glaucoma, PCA applied to quantitative clinical structural and functional parameters returned no groups of clinical parameters that reliably distinguished between patients in IOP-defined glaucoma phenotypes. The present work provides a framework to identify phenotypic groups of glaucoma, the clinical significance of which may vary. We identified the minimum number of test points required to detect central-involving glaucoma in visual field testing. We also demonstrate that IOP-defined phenotypes are not clinically distinguishable at the point of diagnosis, suggesting that these phenotypes form part of a continuum of open-angle glaucoma. These findings have implications for disease staging and preferred treatment modality.