Analysis of Heterochromatin-Associated Genomic Instability
Heterochromatin represents special regions in the genome that have been found to be prone to breakage and rearrangements in cancer cells. Through two separate but related projects on heterochromatin, this dissertation demonstrates the important role of heterochromatin in maintaining genomic integrity. In the first project by transfecting non-coding heterochromatic sequences into cells, a significant increase in genomic instability was induced as demonstrated by increased Comet tails using the Comet assay. In the second project, we developed a more precise approach to measure the size of constitutive heterochromatin bands on human chromosomes. Using this new technique, we have seen increased variability of the heterochromatin regions of chromosomes 1 and 9 in lymphoblastoid cells derived from breast cancer patients as compared to that of age-matched controls. These results indicate that heteromorphisms in the heterochromatin of these chromosomes may be used as a biomarker to identify women with a higher susceptibility to breast cancer. In summary, these observations of heterochromatin- associated genomic instability suggest that heterochromatin regions are fragile sites for breakage and rearrangements and these alterations may act in a cis fashion to promote genomic instability.