DISCOVERY OF NOVEL EPIGENETIC MECHANISMS OF CARCINOGENESIS BY GENOME-WIDE PROFILING OF NON-CODING REGULATORY ELEMENTS

Epigenetic mechanisms are of paramount importance in cancer. Historically, epigenetic studies of cancer have focused on aberrant DNA methylation events. Far less is known about the role of histone modifications in epigenetic mechanisms of human cancers, and of disease in general. There are a number of reasons why histone modifications are especially important to investigate in the context of tumor formation. While DNA methylation contributes to stable gene silencing and formation of heterochromatin, histone modifications are associated with much more dynamic gene expression patterns. Importantly, histone modifications are also informative of the activity states of distal regulatory elements. Therefore we can use these epigenetic marks to study important regions of the cancer genome that are key regulators of transcription with unprecedented resolution and accuracy. In this work, in-depth studies of epigenetic features of both promoters and distal enhancer elements are described, in each case enabled by distinct histone modifications that are chromatin “signatures” of promoter and enhancer elements, respectively. We show that in colon cancer, the presence of the H3K4me3 active mark is associated with resistance to silencing associated with DNA methylation. We further show evidence that in colon cancer, DNA hypermethylation is likely a relatively rare event at CpG-islands, and that most CpG-islands are probably silenced by alternative mechanisms, specifically the acquisition of repressive histone marks. With respect to distal regulatory elements, enhancer elements are especially attractive candidates to study in cancer, a disease of widespread and heterogeneous aberrant transcription, because they are under normal circumstances drivers of cellular identity and associated global gene expression programs. We report the discovery of thousands of Variant Enhancer Loci, or VELs, which have gained or lost H3K4me1 at enhancer elements in colon cancer samples. We show that VELs are tightly linked to the in vivo colon cancer transcriptome, and furthermore are enriched at colon cancer susceptibility SNPs. We propose that the model describing gene dysregulation in cancer be revised to now include epigenetic dysregulation at enhancer elements as an important mechanism in cancer-specific gene expression.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Molecular Medicine

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Akhtar-Zaidi, Batool

Contributors dc:contributor

• Markowitz, Sanford
• Scacheri, Peter

• Biomedical Research
• Epigenetics
• cancer
• enhancer elements

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1347020396

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1347020396