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Title: Mechanisms of 3-dimensional organisation of the human genome
Author: Gilchrist, Susan
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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I have investigated the nuclear distribution of chromosomes in a variety of different primary and transformed cell lines. I have also performed FISH and chromosome position analysis on histological tissue sections. The data suggest that the nuclear organisation in cultured cells reflects that of the nuclei in human somatic cells in vivo. It is possible that chromatin composition, especially histone modifications, are involved in the maintenance of chromosome spatial organisation. Using chemical inhibition of histone deacetylation with the drug Trichostatin-A (TSA), endogenous levels of histone acetylation in the nucleus were disrupted. I have then analysed the position of centromeres and chromosomes in cells treated with TSA. I found no detectable rearrangement of chromatin under these conditions. This suggests that histone acetylation does not play a vital role in influencing the spatial organisation of chromatin. Many nuclear membrane and lamina components have chromatin binding domains and are capable of binding chromatin and/or associated proteins in vitro. Interest in the nuclear lamina and its role in spatial organisation of chromatin has recently increased with the discovery of human ‘laminopathies’, syndromes caused by mutations in lamin A or emerin. Experiments have shown that the spatial organisation of chromosomes is not altered in lymphoblast cells that carry a null mutation of emerin. I have generated stable cell lines over-expressing disease-associated mutations of lamin A protein. Some peripheral chromosomes are no longer present at the nuclear periphery in cells over-expressing lamin A. I also followed the interphase dynamics of different lamin A disease-associated mutants and some mutant proteins are more mobile than the wild-type lamin A in FRAP studies. Many different cells types of the human body arrange the genome in a radial fashion. My observations would suggest that chromatin composition, specifically core histone acetylation, is not the most influential factor on this radial arrangement; what is perhaps more significant is the relative levels of nuclear lamina components.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available