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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/23461
Title: INVESTIGATING NOVEL β-CATENIN SIGNALLING MECHANISMS IN AN EMBRYONIC STEM CELL MODEL
Authors: Abdulla, Solen
Advisor: Doble, Bradley
Department: Biochemistry and Biomedical Sciences
Keywords: β-catenin;Stem Cells
Publication Date: 15-Dec-2017
Abstract: The Wnt/β-catenin pathway is a fundamental regulator of embryonic development and adult tissue homeostasis. The key effector, β-catenin, is a multifunctional protein that occupies dual roles in signalling and intercellular adherens junctions. β-catenin primarily signals though the TCF/LEF transcription factors; however, many transcription factors, in addition to TCF/LEFs, interact with β-catenin, and the function of these interactions is poorly understood. To investigate novel β-catenin regulated signalling mechanisms with certainty, we developed TCF/LEF quadruple knockout (QKO) mESCs. In vitro differentiation of QKO cells reveals a neural differentiation bias, which is attenuated by overexpression of stabilized β-catenin. Our data indicate the presence of a TCF-independent β-catenin regulated neural differentiation blockade in mESCs. In addition to directly challenging the central dogma of canonical Wnt signalling, this finding has the potential to unveil new therapeutic targets for the treatment of many β-catenin-associated diseases, including forms of brain cancer that may arise from the oncogenic stimulation of neural stem cells. Furthermore, we describe an attempt to identify genome-wide TCF-independent β-catenin binding sites in QKO cells by ChIP-seq. Optimization trials provide proof of concept that the fold enrichment method of interpreting ChIP-qPCR results can be highly misleading when compared to the more comprehensive % input method of analysis. This conclusion has important implications for all fields of scientific research in which ChIP-seq methodology is employed.
URI: http://hdl.handle.net/11375/23461
Appears in Collections:Open Access Dissertations and Theses

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