Medical Biology - Theses
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ItemNo Preview AvailableThe role of ING4 and ING5 in cardiac development( 2020)The heart is one of the first organs to develop in a vertebrate embryo. The intricate design of the asymmetric four-chambered organ is reflected in both its structures and mechanics. A healthy functional heart is an amalgamation of precisely aligned great vessels, continuous sheets of trilayered tissues that form the chamber walls and septum, a coordinated conduction system, and an uninterrupted supply of oxygenated blood from the coronary vasculature. At a cellular level, heart morphogenesis is a remarkable feat of tightly regulated cell proliferation, apoptosis, migration and differentiation. These events are driven by spatially and temporally coordinated gene expressions. Post-translational modifications of histone proteins such as acetylation and deacetylation are central to gene expression and repression. The genome site-specific activities of enzymes responsible for acetylation and/or deacetylation rely on protein domains that can recognize and bind to modified histone residues. These protein domains are present in either the histone modifying enzyme itself or adaptor proteins that are present within the histone modifying complex, known as histone ‘reader’ proteins. In this thesis, I have used knockout mice to investigate the roles of two histone reader proteins – ING4 and ING5, both present in histone acetyltransferase complexes in vivo, demonstrating the consequences of loss of these histone reader proteins in the patterning and structural development of the heart. In the first part of my thesis, I have demonstrated that loss of both Ing5 alleles alone did not incur any haematopoietic defects, unlike loss of the proposed histone acetyltransferase enzyme subunit present in the ING5 protein complex. Subsequently, I characterised the survival and appearances of mice with deletion of a combination of Ing4 and Ing5 alleles. I showed that ING4 and ING5 are functionally redundant, as mice died in mid-gestation in the absence of both proteins, whereas mice lacking only ING5 developed to term and mice lacking only ING4 were viable, healthy and fertile. However, mice lacking both Ing5 alleles and one Ing4 allele showed heart development abnormalities with full penetrance and died in utero. In the second part of my thesis, I explored mechanisms underlying the heart development defects observed in the compound mutants. I showed that the epicardium was most vulnerable to the loss of Ing4 and Ing5 alleles. I demonstrated that Ing4+/– Ing5–/– mutant mice were incapable of generating epicardium-derived cells and a proper coronary endothelial network. In addition, I have also demonstrated the redundancy of ING4 and ING5 with respect to gene expression changes and changes in global histone acetylation, further explaining how they possibly control heart development via regulating the functions of their associated histone acetyltransferase enzymes. Overall, my studies provide evidence that ING4 and ING5 are important reader proteins during embryonic development, in particular for the development of the heart and specifically in the epicardium tissue. ING4 and ING5 are likely to exert their functions by targeting the histone acetyltransferase activities of a MYST histone acetyltransferase enzyme to specific gene loci.
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ItemAssessing the role of histone acetylation during development( 2020)This thesis investigates the role of histone acetylation during embryonic development.