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Mapping epigenetic features and cisplatin-induced alterations in cancer genomes

University of British Columbia

Since the completion of human genome sequencing, scientists have attempted to decipher the interactions and distribution of functional elements in the genome in hopes of explaining the mechanisms behind cancer development. Recently, researchers have been studying epigenomics, as the reversible nature of epigenomic alterations has greatly aided the understanding of the underlying mechanisms in tumour development. The major epigenetic events include DNA methylation and histone modifications. The first part of my thesis focuses on studying the interactions among DNA methylation and various histone H3K9 modifications. At any given locus, there are 243 possible patterns of these epigenetic marks. Through global epigenetic mapping, I identified non-random distribution of these patterns and discovered that some specific patterns are more prominent than others. The fact that these histone marks are not distributed equally at large scale suggests that histone modification is not only a small scale phenomenon. To extend studies of modification on DNA, the second part of my thesis focuses on studying cisplatin induced DNA adducts and their clearance. I achieved this by adapting the immunoprecipitation technique that was optimized in the first part of my thesis. My results showed non-random integration of cisplatin on DNA. Furthermore, from global clearance maps, I identified slow drug clearance and rapid drug clearance loci. This implies that there are some adduct formation sites that are being preferentially repaired over others. With more interest on the interaction between chromatin structure and DNA damage, the global maps generated in my thesis provide a critical step in understanding the distribution of these events in the genome, and will contribute to establishing a biological model investigating effects of cisplatin induced alterations on chromatin modification structure.

Thesis/Dissertation

application/pdf

2009-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/12608

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/