title: Integrative methods for epigenetic profiling in cancer and development
creator: Wang, Qi
subject: 500
subject: 500 Natural sciences and mathematics
subject: 570
subject: 570 Life sciences
description: DNA mutation, epigenetic alteration, and gene expression are three major molecular components that distinguish cancer from normal cells. Although it is widely accepted that epigenetic modifications can greatly affect the expression of the target genes, because of the complex combinations of epigenetic marks, together with the interactions between multiple non-coding regulatory elements, measuring the epigenetic effects on gene expression is not an easy task. Nevertheless, it is estimated that epigenetic modifications have a greater effect than DNA mutations on tumorigenesis. In addition, epigenetic alterations are the initiating factor in some chromosome abnormalities and aberrant gene expression, making the study of epigenetic alterations a central aspect in understanding the underlying mechanisms in cancer and cell development. The aim of this thesis is to conduct qualitative and quantitative analyses of differential epigenetic modifications. To this end, a variety of existing approaches were applied in the ChIP-Seq analyses of six histone marks on glioblastoma data from four distinct subtypes. The results depict a comprehensive landscape of active and poised regulatory elements specific to glioblastoma subtypes, which describes the different aspects of tumor progression. However, the descriptive model of multiple histone marks (ChromHMM and peak calls) was also shown to be prone to various biases and artifacts. Moreover, some models also neglect the quantitative information of ChIP-Seq data, making it inadequate in addressing the magnitude of changes between epigenetic modification and gene expression levels. Therefore, in the second part of my work, I designed an integrative, network-based approach, in which I integrated two levels of epigenetic information: the signal intensities of each epigenetic mark, and the relationships between promoters and distal regulatory elements known as enhancers. Applying this approach to a variety of test cases, it predicts a number of candidate genes with significant epigenetic alterations, and comprehensive benchmarking validated these findings in cancer and cell development. In summary, as increasing amounts of epigenetic data become available, the computational approaches employed in this study would be highly relevant in both comparative and integrative analysis of the epigenetic landscape. The discovery of novel epigenetic targets in cancers, not only unfolds the fundamental mechanisms in tumorigenesis and development, but also serves as an emerging resource for molecular diagnosis and treatment.
date: 2018
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/25481/7/Wang_Qi_thesis.pdf
identifier: DOI:10.11588/heidok.00025481
identifier: urn:nbn:de:bsz:16-heidok-254816
identifier:   Wang, Qi  (2018) Integrative methods for epigenetic profiling in cancer and development.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/25481/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng