Investigating the miRNA pathways contribution to intra-tumour heterogeneity in glioblastoma and RNA binding of isoforms of the miRNA effector protein Argonaute

Smith, Christopher Michael

Investigating the miRNA pathways contribution to intra-tumour heterogeneity in glioblastoma and RNA binding of isoforms of the miRNA effector protein Argonaute

Smith, Christopher Michael

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Publication Type:: Thesis
Issue Date:: 2022

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Field	Value	Language
dc.contributor.author	Smith, Christopher Michael
dc.date.accessioned	2023-03-30T23:14:07Z
dc.date.available	2023-03-30T23:14:07Z
dc.date.issued	2022
dc.identifier.uri	http://hdl.handle.net/10453/168903
dc.description	University of Technology Sydney. Faculty of Engineering and Information Technology.	en_US.UTF-8
dc.description.abstract	miRNAs are highly abundant small non-coding RNAs that are essential for post-transcriptional gene regulation. Many of the mechanisms which regulate miRNA expression and function are poorly understood. Their dysregulation is documented extensively in many diseases including cancer. Glioblastoma is a highly aggressive and heterogeneous brain cancer that affects patients of all ages. Intra-tumoural heterogeneity describes the existence of genomically distinct subpopulations of tumour cells which can lead to differences in growth rate, metastatic potential, or vulnerability to certain treatments. The first part of my thesis investigates how miRNAs and miRNA variants (isomiRs) may be involved in intra-tumoural heterogeneity by applying bioinformatics analyses to single cell small RNA and RNA sequencing data generated from previous studies. This work identified two miRNA clusters, the Dlk1-Dio3 locus and miR-224/452, as potential contributors to intra-tumour heterogeneity in glioblastoma and may be involved in cell state regulation. Additionally, we found evidence of cell autonomous regulation and function of isomiRs, highlighting another regulatory mechanism that may play a role in heterogenous cancers. These miRNAs may have utility as cancer biomarkers and implicate a novel set of targets for therapeutic research. The second part of my thesis investigates splice variants (isoforms) of Argonaute, an essential protein in the miRNA pathway that mediates their regulatory effects. Numerous Argonaute isoforms have been previously annotated, with alterations in protein domains critical for miRNA binding and function. However, current studies base their assumptions of miRNA activity through a single variant of Argonaute and the consequence of these alterations and their biological relevance has not been investigated yet. We identified two variants of Argonaute with altered miRNA binding characteristics that are variably expressed in normal and cancerous cells, revealing a novel form of miRNA regulation that could also have implications in cancer research.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/168903/1/02whole.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2022 Christopher Michael Smith
dc.rights	au.edu.uts.lib/ppc
dc.title	Investigating the miRNA pathways contribution to intra-tumour heterogeneity in glioblastoma and RNA binding of isoforms of the miRNA effector protein Argonaute	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

miRNAs are highly abundant small non-coding RNAs that are essential for post-transcriptional gene regulation. Many of the mechanisms which regulate miRNA expression and function are poorly understood. Their dysregulation is documented extensively in many diseases including cancer. Glioblastoma is a highly aggressive and heterogeneous brain cancer that affects patients of all ages. Intra-tumoural heterogeneity describes the existence of genomically distinct subpopulations of tumour cells which can lead to differences in growth rate, metastatic potential, or vulnerability to certain treatments. The first part of my thesis investigates how miRNAs and miRNA variants (isomiRs) may be involved in intra-tumoural heterogeneity by applying bioinformatics analyses to single cell small RNA and RNA sequencing data generated from previous studies. This work identified two miRNA clusters, the Dlk1-Dio3 locus and miR-224/452, as potential contributors to intra-tumour heterogeneity in glioblastoma and may be involved in cell state regulation. Additionally, we found evidence of cell autonomous regulation and function of isomiRs, highlighting another regulatory mechanism that may play a role in heterogenous cancers. These miRNAs may have utility as cancer biomarkers and implicate a novel set of targets for therapeutic research. The second part of my thesis investigates splice variants (isoforms) of Argonaute, an essential protein in the miRNA pathway that mediates their regulatory effects. Numerous Argonaute isoforms have been previously annotated, with alterations in protein domains critical for miRNA binding and function. However, current studies base their assumptions of miRNA activity through a single variant of Argonaute and the consequence of these alterations and their biological relevance has not been investigated yet. We identified two variants of Argonaute with altered miRNA binding characteristics that are variably expressed in normal and cancerous cells, revealing a novel form of miRNA regulation that could also have implications in cancer research.

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http://hdl.handle.net/10453/168903