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An investigation of the roles of GATA4 and its target genes in cardiac differentiation of iPS Cells

Graham, Nicola 2023. An investigation of the roles of GATA4 and its target genes in cardiac differentiation of iPS Cells. PhD Thesis, Cardiff University.
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Heart development and homeostasis are controlled by the collective action of numerous transcription factors (TFs), that come together to form complex and dynamic gene regulatory networks (GRN) that define and maintain cellular identity. Disruption of the cardiac GRN is associated with the development of congenital heart defects (CHDs), and cardiovascular disease (CVD) in later life. Yet, our knowledge of the TFs that contribute to the GRN and their target genes is incomplete. The TF GATA4 has been established as a core member of the cardiac GRN with roles throughout heart development and the adult heart. Therefore, the genes regulated by GATA4 are likely involved in these processes too. Using Xenopus laevis embryos to model cardiac development two genes were identified and validated: tbx2 and prdm1, as Gata4 targets. However, it was not known whether this regulatory relationship was conserved in human cardiac development and whether these genes themselves are required for normal heart development. The work presented in this thesis addresses this with the creation of GATA4, TBX2, and PRDM1 mutant human iPSC lines using CRISPR-Cas9 gene editing. The results presented demonstrate that GATA4 is absolutely essential for the formation of cardiomyocytes (CMs) from iPSCs, which has not previously been examined in depth in a human model of cardiomyogenesis. It is also demonstrated that TBX2 and PRDM1 are differentially regulated in the absence of GATA4, indicating this regulatory relationship is likely conserved between Xenopus and humans. Furthermore, it is demonstrated that TBX2 and PRDM1 are modulators of the cardiac transcriptome. Separately the role of GATA6, a TF that is closely related to GATA4, is investigated. GATA6 has recently been shown to be essential for iPSC-CM differentiation. The results presented herein add to this by showing that removal of a GATA6 regulatory domain disrupts normal iPSC-CM differentiation. Together these investigations expand our knowledge of what nodes in the cardiac GRN are required for normal cardiac development, and therefore what elements may factor into the development of CHDs and CVDs.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 8 February 2024
Last Modified: 08 Feb 2024 14:48

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