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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2018

Month Degree Awarded

September

First Advisor

Jesse Mager

Subject Categories

Developmental Biology

Abstract

Mammalian development involves remarkable changes, starting from a single-cell, totipotent zygote and ending with a developed organism comprised of diverse cells types with distinct morphologies, structures, and functions. Within three days of murine development, the two parental genomes merge into a single nucleus, begin zygotic gene expression, undergo epigenetic remodeling, and make the first lineage decisions. Diversity in cell-types is possible even though cells share the same genome. This diversity is achieved by the tight regulation of differential transcriptional programs. There are many ways these transcriptional programs can be initiated. Epigenetic alterations to the genome can drive transcriptional changes.

Epigenetic changes can influence expression for any gene across the whole genome; however, one epigenetic phenomenon that only affects a small subset of loci is genomic imprinting. Defined as mono-allelic gene expression in a parent-of-origin manner, imprinting is interesting because 1) epigenetic marks at imprinted sites differ between the two parental haploid genomes, 2) the epigenetic marks persist past fertilization, following the merger of the two parental genomes, 3) imprinted epigenetic marks escape epigenetic reprogramming during development, and 4) when misregulated, can lead to disease states.

At the most basic level, imprinting makes an excellent system for studying epigenetic phenomenon in general; having both an active and repressed allele in the same nuclear environment allows for examination of the epigenetic requirement to maintain those states. Studying imprinting has highlighted the role DNA methylation can play in regulating genes in cis, how long non-coding RNAs function in the genome, and how long-range, chromatin looping can regulate expression. Imprinting is also medically relevant; there are multiple human disorders linked to aberrant imprinted expression. Additionally, imprinting can be used as an epigenetic readout to improve reprogramming techniques including induced pluripotent stem cell (iPCs) and somatic cell nuclear transfer (SCNT), as well as assessing the quality of embryos created by artificial reproductive technology (ART).

The goal of this thesis is to characterize imprinted expression during early embryonic development. Here, I will define a novel spectrum of imprinted expression and epigenetic dynamics, which should inform both basic biology and applied technologies.

Available for download on Sunday, September 01, 2019

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