Abstract

The human placenta undergoes rapid development through highly coordinated changes to serve a range of physiological roles. For example, Cytotrophoblasts (CTBs) cells of the placenta undergo molecular changes allowing them to invade the uterine wall and remodel maternal spiral arteries. Syncytiotrophoblasts (STBs) are multinucleated cells that produce the hormones necessary to sustain pregnancy. In placental diseases such as severe Preeclampsia (sPE), we observe a deviation of CTBs and STBs from their physiological roles, but the underlying mechanisms of sPE remain poorly defined. While the transcriptome of the placenta has been profiled; however, epigenetic modifications that regulate the transcriptome had not been comprehensively studied during gestation and in placental pathologies. In this regard, the CTB and STB epigenomes will be informative to identify epigenetic mechanisms that regulate placental development and disease. To this end, I explored how DNA methylation, chromatin accessibility and 3D-genome interactions change during gestation and how these changes impact gene expression. We used the findings from normal pregnancy to determine how the epigenome and corresponding transcriptome deviate in placental pathology: severe preeclampsia (sPE). The genome-wide hypomethylation of CTBs and the unique properties of the placenta present an opportunity to study Transposable Elements (TEs), which can function as cis-regulatory elements in hypomethylated tissues, such as cancer cells. TEs can provide genetic material to facilitate rapid genome evolution in a highly divergent organs, such as the placenta, and contribute to the 3D genome through enhancer-promoter interactions. While a few examples of placenta-specific TE-derived cis-regulatory elements demonstrate the potential for TEs to contribute to the placenta regulatory landscape, the genome-wide potential of TEs as cis-regulatory elements in CTBs remains unknown. To address this knowledge gap, we assessed the TE landscape and contribution as cis-regulatory elements during gestation and in sPE for CTBs. This thesis defined the distinct profiles of CTB and STB epigenomes and transcriptomes in normal and placental pathology: sPE. This work also defined TE contributions as cis-regulatory elements. These studies provided greater insights into potential epigenetic mechanisms and TE contributions to gene regulation in placenta development. Overall, these studies improved our knowledge of trophoblast biology during normal pregnancy and identified known and novel pathways associated with sPE. This work equipped researchers and clinicians with information that could be further studied to improve pregnancy outcomes. Lastly, in collaboration with members of the Challen lab, we determined the role of DNA methyltransferase, DNMT3a, in hematopoietic stem cells. Despite DNMT3a being a methyltransferase enzyme, loss of function studies showed few DNA methylation dependent changes that correlated with gene expression. Thus, we explored DNA methylation independent functions of DNMT3a in hematopoiesis using a mouse model. We found Dnmt3a-null hematopoietic stem cells have increased telomerase activity, which serves as a protection from telomere shortening and contributing to stem cell longevity.

Committee Chair

Ting Wang

Committee Members

Jacqueline Payton; John Edwards; Joseph Costello; Susan Fisher; Thorold Theunissen

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-11-2026

Language

English (en)

Download

Available for download on Tuesday, August 10, 2027

Included in

Genetics Commons

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