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.

Date of Award

Summer 8-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

In mammals, DNA methylation is essential for development, and helps determine cell identity in over 200 specialized cell types. Dynamic CpG methylation during cell differentiation is correlated with changes in gene regulation and expression, with loss of methylation typically reflecting enhancer or gene activation. In this work, I identify and characterize unusual signatures in the human methylome that reveal unique modes of cell type-specific gene regulation.

Most CpGs in the genome are fully methylated or unmethylated, implying a binary relationship with gene expression. In the first part of this thesis, I discover regions of intermediate DNA methylation (IM) in the genome that exhibit variable methylation between alleles or cells in a population of uniform cell type. Thousands of IM regions are identified in multiple cell types, and are conserved across tissues, individuals, and species. The IM state is associated with intermediate levels of gene expression and exon usage, indicating a potential mechanism of quantitative gene regulation.

I then conduct an in-depth examination of the enigmatic human placenta epigenome, which has unusually low levels of DNA methylation similar to those observed in tumors. Integration of whole-epigenome and transcriptome data reveals that different histone modifications distinguish active and repressed genes in the absence of DNA methylation. This implies the existence of DNA methylation-independent regulatory mechanisms unique to the placenta genome.

These studies demonstrate the utility of high-throughput epigenomic data analysis in understanding the role of DNA methylation in development. Additionally, they support a relationship between epigenetic modification and gene regulation that is more nuanced and pliable than previously thought.

Language

English (en)

Chair and Committee

Gary D Stormo

Committee Members

John R Edwards, Barak A Cohen, Heather A Lawson, ,

Comments

Permanent URL: https://doi.org/10.7936/K70Z71BF

Available for download on Thursday, August 15, 2115

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