This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

ORCID

http://orcid.org/0000-0001-9654-4448

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Deciphering how epigenetic factors, such as DNA methylation and chromatin accessibility, shape normal development and disease progression has been an outstanding goal in developmental biology. Here, I present multiple branches of my thesis to elucidate the epigenetic controls that direct aging in brain, regulate cell fate decision of zebrafish iridophore in pigment differentiation, and dysregulate transposable elements (TEs) in cancer. The first branch focuses on benchmarking a computational statistic tool to characterize DNA methylation dynamics of aging in mouse prefrontal cortex by combining WGBS and TAB-seq to dissect the contribution of CpG methylation and hydroxymethylation. For the second branch, we take advantage of the elegant zebrafish model system to answer how epigenetic dynamics shape pigment development. We developed conditional CRISPR knockout method, which if combined with clonal analysis, can provide temporal and cell lineage-specific resolution. Furthermore, we profiled DNA methylation, chromatin accessibility, and gene expression across various biological timepoints of neural crest differentiation to pigment cells in zebrafish. Here, I focus on exploring the genetic and epigenetic dynamics that drive iridophore cell fate. In the third branch, TEs are an underexplored genetic resource that impact both normal development and disease. Especially in the context of cancer, recent discoveries exemplify how particular TEs are epigenetically reactivated to provide enhancer or promoter regulatory roles, known as onco-exaptation, that contribute to oncogenesis. One example is the reactivation of cryptic promoters in TEs that provide alternative transcription start sites (TSS) for oncogenes. These alternative TSSs can generate chimeric or truncated oncogene transcripts that could accelerate tumorigenesis. However, TEs may be a double-edged sword for cancer, as aberrant TE activation can provide additional sequences to be translated into novel peptides that can be used as biomarkers or targets for immunotherapy through cancer vaccines or enhanced T cell therapy. Recent work has revealed that epigenetic therapy (epitherapy) can preferentially activate epigenetically silenced TEs, which generates epitherapy-specific transcripts and potential novel cancer-specific antigens that can be exploited as therapeutic targets for immunotherapy. I aim to study the prevalence of onco-exaptation events across numerous cancer types and explore potential immunotherapeutic approaches by exploiting TE-specific transcripts in the glioblastoma in the presence of epitherapy.

Language

English (en)

Chair and Committee

Ting Wang

Committee Members

Charles K. Kaufman,Albert H. Kim, Rob Mitra, Tim Schedl

Available for download on Monday, May 15, 2023

Included in

Genetics Commons

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