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Methylome Sequencing Reveals the Context-Specific Functions of DNA Methylation in Indolent Versus Aggressive Prostate Cancer

Bhasin, Jeffrey M
http://orcid.org/0000-0001-6134-1982
http://rave.ohiolink.edu/etdc/view?acc_num=case148120498969955

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Elucidating the molecular determinants of aggressive prostate cancer has major implications for developing molecular diagnostics that, in conjunction with clinicopatholgic variables, can be used to risk-stratify patients more accurately. We hypothesized that DNA methylation can distinguish indolent from aggressive prostate cancer through aberrant gene regulation. This thesis presents the novel bioinformatics tools needed to pursue this hypothesis, a methylome analysis in aggressive prostate cancer, evidence for genomic context-specific functional interpretations of DNA methylation, data from a model system regarding a role for DNA methylation in regulating alternative cleavage and polyadenylation (APA), and integration of differential methylation data with a machine learning predictor of prostate cancer histology. We found focal DNA hypermethylation can distinguish indolent, low Gleason grade prostate cancer from aggressive, high grade disease using the genome-wide MBD-isolated genome sequencing technique. Notably, high grade DMRs occurred not only in the promoters of genes, but also in gene bodies and intergenic regions highly enriched for DNaseI hypersensitivity, annotated enhancers, and DNA-protein binding sites. DNA methylation also correlates with reduced gene expression for genes where low expression associates with poorer outcomes. By analyzing genic DMRs in a pathway network, we detected common cancer-related signatures between shared and high grade DMR genes. We further extended our analysis to consider connections with alternative transcript usage. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we correlated DNA methylation changes with alternative exon usage in aggressive prostate cancer. Following an observation that prostate cancer DMRs show enrichment in gene 3' ends, we used a model system with genomic depletion of DNA methylation to consider if DNA methylation can regulate alternative cleavage and polyadenylation (APA). We related candidate genes from this analysis back to prostate cancer via correlations based on TCGA RNA-seq data, and further found evidence for these associations by using data across developmental lineages in the Epignome Roadmap Project. We also employed machine learning methods to identify if any DMRs occur proximal to genes that can predict Gleason score. This catalog of high grade DMRs can be used to guide mechanistic studies into how DNA methylation alters gene regulation that leads to aggressive cancer.
Angela Ting, PhD (Advisor)
Thomas LaFramboise, PhD (Committee Chair)
Eric Klein, MD (Committee Member)
Jonathan Smith, PhD (Committee Member)
Alex Almasan, PhD (Committee Member)
204 p.
Bioinformatics; Biomedical Research; Genetics; Molecular Biology
DNA methylation; epigenomics; bioinformatics; prostate cancer; differentially methylated regions; gene expression; gene regulation; epigenetics; molecular medicine; alternative cleavage and polyadenylation; genomic context; genomics;

Recommended Citations

Citations

  • Bhasin, J. M. (2016). Methylome Sequencing Reveals the Context-Specific Functions of DNA Methylation in Indolent Versus Aggressive Prostate Cancer [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case148120498969955

    APA Style (7th edition)

  • Bhasin, Jeffrey. Methylome Sequencing Reveals the Context-Specific Functions of DNA Methylation in Indolent Versus Aggressive Prostate Cancer. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case148120498969955.

    MLA Style (8th edition)

  • Bhasin, Jeffrey. "Methylome Sequencing Reveals the Context-Specific Functions of DNA Methylation in Indolent Versus Aggressive Prostate Cancer." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case148120498969955

    Chicago Manual of Style (17th edition)

case148120498969955
277
© 2016, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.