Date of Award
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular, Molecular and Biomedical Sciences
First Advisor
Seth Frietze
Abstract
Breast cancer, known for its global impact and heterogeneity, involves both geneticand epigenetic alterations that malignantly transform breast epithelial cells. Among these changes, epigenetic modifications, particularly post-translational histone modifications (PTMs), are now recognized as potential therapeutic targets. Despite this, a full understanding of epigenetic regulation, specifically altered landscape of PTMs during breast tumor development, is still evolving. This dissertation aims to elucidate the global patterns of PTMs in the context of breast cancer development, employing molecular datasets integrated with bioinformatic analyses to examine the epigenomic landscape within the MCF10 breast tumor progression model. Graph analysis is also applied to deconstruct histone modification profiles, providing insight into their functions in breast tumor development. The first section details the regulatory PTM enrichment profiles in the MCF10 model, which simulates various stages of breast cancer development. Utilizing the Peaksat package in R, high-quality ChIP-seq data is captured. An integrated analysis of this dataset delineates chromatin states of breast cells, shedding light on the dynamic shifts in cis-regulatory elements during cancer genesis. This segment emphasizes the transformation of heterochromatin and enhancer domains that govern gene expression and pathway modulation in breast cancer cells, with further analysis revealing the regulatory networks and pinpointing key transcription factors as possible targets for therapy. Besides PTM landscape, the role of Bromodomain-containing (BRD) proteins, known acetyllysine ’readers’ and critical to transcriptional machinery, has not been systematically studied in the context of breast cancer. The latter portion of this dissertation provides an in-depth analysis of BRD proteins’ roles in cancer progression and treatment. A thorough examination of protein-protein interaction (PPI) profiles through graph analysis leads to predictions of functions for previously uncharacterized proteins, underscoring the vital role of BRD proteins in chromatin regulation. In essence, this dissertation advances our comprehension of the epigenomic regulation of breast cancer and unveils new avenues for therapeutic interventions.
Language
en
Number of Pages
282 p.
Recommended Citation
Gao, Cong, "Epigenomic Landscape Profiling and Bioinformatics Application in Breast Cancer Model" (2024). Graduate College Dissertations and Theses. 1840.
https://scholarworks.uvm.edu/graddis/1840