THESIS
2020
ix, 75 pages : color illustrations ; 30 cm
Abstract
Transposable elements comprise of about half of the human genome, with the majority being retrotransposons. These sequences are generally repressed by host epigenetic mechanisms due to their potentially deleterious effects. Aberrant activities of retrotransposons are associated with many diseases including cancer, where dysregulated elements function as regulatory elements, such as promoters and enhancers to affect the transcription of adjacent genomic regions. In particular, a number of previous studies have reported abnormal retrotransposon activities in melanoma, a malignant skin cancer originating from melanocytes. However, comprehensive analyses of the underlying molecular mechanisms have not been conducted. In this study, I aim to delineate the epigenomic dysregulation of retrotra...[
Read more ]
Transposable elements comprise of about half of the human genome, with the majority being retrotransposons. These sequences are generally repressed by host epigenetic mechanisms due to their potentially deleterious effects. Aberrant activities of retrotransposons are associated with many diseases including cancer, where dysregulated elements function as regulatory elements, such as promoters and enhancers to affect the transcription of adjacent genomic regions. In particular, a number of previous studies have reported abnormal retrotransposon activities in melanoma, a malignant skin cancer originating from melanocytes. However, comprehensive analyses of the underlying molecular mechanisms have not been conducted. In this study, I aim to delineate the epigenomic dysregulation of retrotransposons using melanoma cell lines as models. By employing a combination of molecular epigenetic approaches and bioinformatic analyses, I found that retrotransposons in melanomas are dramatically DNA hypomethylated and exhibit alterations in histone modification enrichment. Furthermore, these dysregulated retrotransposons have the potential to be regulatory elements and are able to affect transcription of adjacent genomic regions. Dozens of melanocyte-specific and melanoma-specific retrotransposon-derived novel unannotated RNA transcripts were discovered and experimentally validated. Interestingly, a potential repression mechanism for epigenetically dysregulated retrotransposons in melanomas mediated by a transcription factor, Bach1, is proposed; as well as the finding of a melanoma-specific Bach1 novel isoform which is not annotated previously. Taken together, this study serves to improve our understanding of the epigenetic mechanisms that regulate repetitive elements and their roles in cancer development. The results may shed light on disease pathogenesis and provide insights into novel biomarker screening and therapeutic target discovery for melanoma.
Post a Comment