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Title: Investigation of epigenetic alterations related to telomere maintenance in human cells
Author: Williams, Jonathan Peter
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2012
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Human telomeres can be maintained by the enzyme telomerase, which catalyses the addition of telomere repeats, or by the Alternative Lengthening of Telomeres (ALT) mechanism, which is recombination based. Recently, knockout mouse cell lines have indicated that epigenetic modifications associated with telomeric and subtelomeric chromatin, including DNA methylation, Histone 3 Lysine 9 (H31K9) trimethylation and Histone 4 Lysine 20 (H4K20) trimethylation, play an important role in influencing the choice of telomere maintenance mechanism. In this thesis, the levels of these modifications were studied in telomeric chromatin and in the telomere adjacent chromatin of the short arm of the human sex chromosomes (XpYp) in a panel of six human cell lines utilising different telomere maintenance mechanisms. In marked contrast to mouse models, no relationship was found between the level of any of these modifications and telomere maintenance pathway. This may indicate that the role such marks play at telomeres differs between humans and mice. Additionally, the level of chromatin modifications associated with binding of 53BP1 was not affected by the telomere maintenance mechanism used in human cell lines. Similarly, H3K9 and H4K20 trimethylation adjacent to the MS32 minisatellite did not show ALT-specific alterations despite the high level of instability at this locus in ALT positive cells. Subtelomeric DNA methylation in the mouse has been shown to have a dynamic relationship with telomere length. In the current study, this relationship was investigated in telomerase positive human cells using a DNA methylation sensitive variant of the Single Telomere Length Analysis (STELA) technique. No relationship between telomere length and DNA methylation at XpYp was found in telomerase positive cells. Additionally, ectopic expression of telomerase in primary human fibroblasts did not alter subtelomeric DNA methylation. However, evidence suggests that elongated telomeres can prevent loss of subtelomeric DNA methylation associated with replication in normal human cells.
Supervisor: Royle, Nicola Sponsor: BBSRC funding
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available