Molecular Consequences of High Taz Expression In Gliomas

<p>Diffuse high grade gliomas are complex and lethal neoplasms of the adult central nervous system that are driven by a range of genetic and epigenetic alterations. Molecular classification of these tumors has identified different transcriptional subtypes, the most notable being Proneural (PN) and Mesenchymal (MES) classes. The most aggressive forms of the disease have a Mesenchymal expression signature, with reported PN-to-MES transition occurring with tumor progression. Master regulatory analysis has identified the transcriptional co-activator TAZ (WWTR1) as a major driver of the MES transition. Overexpression of this single protein in glioma stem cells has been shown to drive a transition from a PN to MES cell state. In this study, we explore in depth the consequences of high TAZ expression in clinical glioma samples. We show that TAZ-high gliomas associate with immune infiltration and extracellular matrix genes, whereas TAZ-low gliomas associate with neuronal development genes. Furthermore, TAZ overexpression causes widespread epigenetic alterations in the cell, with consequent silencing of neuronal differentiation factors and an activation of mesenchymal regulators. Directed differentiation of glioma stem cells towards the post-mitotic neuronal state have been shown to be efficient strategies to battle this disease. By establishing the role of TAZ in suppressing the neuronal state in these cells, we argue that silencing of TAZ and/or its effector molecular complexes through therapeutics is a viable strategy. Given that TAZ has been found to be largely dispensable for normal tissue homeostasis, directed targeting of this protein is an attractive potential avenue in finding a cure for GBM.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2019

Authors dc:creator

• Ravikumar, Visweswaran
• <p>https://www.orcid.org/0000-0003-4670-3898</p>

Contributors dc:contributor

• Arvind Rao
• Krishna Bhat
• Jason Huse

• GBM
• TAZ
• gliomas
• proneural to mesenchymal transformation
• epigenetics
• ChIP-seq
• Bioinformatics
• Computational Biology
• Genomics
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/974

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2022