Degree Type

Thesis

Date of Award

2020

Degree Name

Doctor of Philosophy

Department

Genetics, Development and Cell Biology

Major

Bioinformatics and Computational Biology

First Advisor

Geetu Tuteja

Abstract

The placenta is formed early in pregnancy and plays a crucial role during its short existence, providing nutrients, hormones, and protection throughout pregnancy. For the placenta to function and develop properly, precise spatiotemporal expression of genes is critical. Abnormal gene expression can lead to adverse pregnancy outcomes and disease such as preeclampsia, hyperemesis gravidarium, placental abruption, and miscarriage. However, placental gene regulatory networks, that when disrupted could contribute to such outcomes, are poorly understood. Using the mouse as a model, we generated and analyzed several next generation sequencing datasets to better understand transcriptional regulation in the placenta. First, we generated chromatin accessibility data and integrated it with transcriptomic data to identify gene networks associated with important aspects of placental function, as well as gain insights into potential regulatory mechanisms of such genes. We also developed a pipeline for identifying genes important for development by analyzing their expression and promoter accessibility. Next, we generated epigenetic data, allowing us to identify cis-regulatory regions genome-wide and predict their biological role during a critical stage of development, when abnormal gene expression commonly causes embryonic lethality. Lastly, we were able to identify a novel angiogenic role for the PLAGL1 transcription factor within the placenta. Combining transcriptomic data with enhancer marks, we were able to computational predict that PLAGL1 regulated enhancers targeting genes involved in blood vessel development. We then performed several molecular experiments in order to verify such predictions. Each aspect of this work furthers our knowledge on placental gene regulation by identifying regulatory regions, their targets, and their controlling transcription factors which may be critical for proper placental function.

DOI

https://doi.org/10.31274/etd-20210114-144

Copyright Owner

Rebekah Starks

Language

en

File Format

application/pdf

File Size

173 pages

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