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Integrative Analysis of Prostate Cancer Methylome and Smoking-induced Transgenerational Epigenomic Reprogramming

Gu, Lei

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Epigenetic factors such as DNA methylation, histone modification and noncoding RNAs are highly associated with early developmental processes, later environmental adaption and diseases development such as cancer. With the availability of current high throughput assays (microarray and next generation sequencing), one can already produce comprehensive picture of the epigenetic profile, especially the DNA methylome, in normal and tumor/diseased cells. However, managing and analyzing such vast datasets is challenging. In addition, interpretation of the observations from (epi)genetic information is also a limiting factor due to the lack of understanding epigenetic mechanisms and the interactions between genetic and epigenetic factors under environmental selection. Thus, during my PhD studies, two pipelines were developed to process genome-wide methylation data generated by Methyl-CpG-immunoprecipitation sequencing (MCIP-seq) for the ICGC early onset prostate project and whole genome bisulfite sequencing (WGBS) for the environment induced transgenerational epigenetic remodeling project. The WGBS pipeline was adjusted later for a modified WGBS protocol, tagementaion-based WGBS, which allows to investigate the whole methylome (around 27 million CpGs) at single base resolution by using only 10-20 ng of input DNA compared to 3-5 ug required for traditional WGBS. Developing these computational tools, provided an opportunity to look closely at methylation changes in prostate cancers. With an integrative meta-analysis of public prostate (epi)genomic data and a large cohort of 7682 prostate cancer specimens, BAZ2A was found to be overexpressed in a large subset of prostate tumors that are characterized by early post-operative PSA recurrence and high tumor grades. In multivariate analyses, BAZ2A was found to be an independent factor predicting recurrence. Furthermore, high levels of BAZ2A were tightly associated with a distinct molecular subtype demarked by aberrant genome-wide DNA methylation and elevated numbers of genetic alterations suggesting a CpG island-methylator phenotype (CIMP) to selectively occur in BAZ2A-upregulated tumors. In summary, this study showed the clinical impact of BAZ2A as a key epigenetic regulator linking aberrant DNA methylation and outcome in prostate cancer. In addition, epigenetic changes is not only important for the diseased individuals including cancer, but also for the healthy individuals to adapt the external environmental stimulus such as smoking. In order to investigate the interaction between the methylome and environmental factor in a human prospective mother-child study at single base resolution, tobacco smoke-induced changes to epigenetic programming during the prenatal period was studied by WGBS and targeted methylation analysis. In mothers and children a distinct, genome-wide epigenetic response is induced. While mothers showed a genome-wide hypomethylation profile, children revealed tobacco-smoke induced hyper- and hypomethylation. By focusing on chromatin regulators, differential DNA methylation with functionally deregulated histone modifiers was linked, which together induce epigenetic reprogramming upon exposure to tobacco smoking. Together with the observed deregulation of a number of disease related pathways, the identified aberrant DNA methylation was suggested as a possible molecular mechanism linking between prenatal exposure and disease outcomes later in life. In summary, comprehensive epigenomic analyses were performed on both diseased and healthy individuals in order to shed a light on how epigenetic factors influence the tumor development and interact with external environmental stimulus.

Item Type: Dissertation
Supervisor: Eils, Prof. Dr. Roland
Publisher: Heidelberg University
Place of Publication: Heidelberg, Germany
Date of thesis defense: 19 December 2013
Date Deposited: 13 Jan 2014 08:27
Date: 2013
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
Controlled Keywords: epigenetics, bioinformatics, methylation
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