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Characterising the role of Zeb1 in the adult haematopoietic system

Almotiri, Alhomidi 2019. Characterising the role of Zeb1 in the adult haematopoietic system. PhD Thesis, Cardiff University.
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Zeb1, a zinc finger E-box binding EMT transcription factor, acts as a critical regulator of cell plasticity and confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in somatic stem cells. We have used the haematopoietic system, as a well-established paradigm of stem cell biology, to explore Zeb1 mediated regulation of somatic stem cells. Here, we employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult haematopoietic stem cells (HSCs) and their downstream progeny. Long-term loss of Zeb1 resulted in an expansion of HSCs and MPPs that impacted the differentiation to downstream progenitors, while acute deletion of Zeb1 resulted in a reduction of lymphoid progenitors in BM and no change was observed in HSCs. Transplantation of HSCs after acute and chronic loss of Zeb1 resulted in a profound self-renewal defect and multi-lineage differentiation block. Acute loss of Zeb1 in HSCs activates a transcriptional program of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs. Furthermore, acute deletion of Zeb1 led to a rapid onset thymic atrophy and cell autonomous loss of thymocytes and T cells. This defect in thymocytes was associated with increased cell death and changes in cell cycle kinetics as well as perturbations of memory CD8+ T cell homeostasis. Thus, Zeb1 acts as a crucial transcriptional repressor in haematopoiesis, co-ordinating HSC self-renewal and multi-lineage differentiation fates.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Date of First Compliant Deposit: 17 December 2019
Last Modified: 26 Mar 2021 16:09

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