ORCID
https://orcid.org/0000-0003-2243-9375
Date of Award
Winter 12-15-2016
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Epigenetic features at regulatory elements provide instructive cues for transcriptional regulation during development. However, the particular epigenetic alterations necessary for proper cell fate acquisition and differentiation are not well understood. This dissertation explores the epigenetic dynamics of regulatory elements during development and uses epigenome annotations to document inappropriate transcriptional regulation in disease. First, I summarize my contributions to developing a new algorithm for detecting differential DNA methylation, M&M. I report the application of the M&M algorithm to identify distinct classes of DNA methylation dynamics in surface ectoderm (SE) progenitor cells and SE-derived lineages: epigenome alterations, and differential DNA methylation in particular, that are present in progenitor cells are transmitted to daughter cells and consequently observed in differentiated cells. I exploit this property of DNA methylation to characterize DNA methylation dynamics in surface ectoderm embryonic tissue and SE-derived cells. Next, I use zebrafish to investigate the biological relevance of the classes of DNA methylation dynamics described in the SE context. In zebrafish, I use the pigment cell development system to understand the contribution of DNA methylation to a particular cell fate choice: melanocyte or iridophore cell fate. Next, I investigate the consequence of somatic mutations in primary liver cancer by utilizing epigenomic annotations of human tissues to distinguish putatively functional mutations from passenger mutations. Here I present support for the hypothesis that transcriptional regulatory instructions for heterologous cell types are co-opted by cancer cells during malignant tumorigenesis. Finally I present a review of the evolution of epigenetic regulation over regulatory elements. Altogether, this dissertation advances our understanding of epigenetic regulation in cell fate decisions by integrating functional genomics with developmental biology and cancer genetics.
Language
English (en)
Chair and Committee
Ting Wang
Committee Members
Sarah Elgin, Stephen L. Johnson, Samantha Morris, Nancy Saccone
Recommended Citation
Lowdon, Rebecca Faith, "Epigenomics of Cell Fate in Development and Disease" (2016). Arts & Sciences Electronic Theses and Dissertations. 996.
https://openscholarship.wustl.edu/art_sci_etds/996
Comments
Permanent URL: https://doi.org/10.7936/K7KW5DGM