Abstract

Transposable elements (TEs), traditionally known as “jumping genes”, are known to have the ability to move in the genome and alter the activation of transcriptions from nearby genes. Taking up nearly half of the human genome, TEs have evolved, and some have been selected to play important roles in biological processes. We found that in human diseases such as cancer, global hypomethylation resurrects many ordinarily silenced TEs. These TEs can often serve as alternative promoters for oncogenes and play functionally meaningful roles in driving disease processes. One of the top genetic mutation status that correlates with differential numbers of TE transcripts is p53. In the absence of WT p53, we observed a higher number of TE-derived transcripts. The first part of my thesis is to investigate the regulatory relationship between p53 and TEs. Comprehensive profiling of TE-derived transcript dynamics under the regulation of p53 provides valuable resources for more clarity in p53’s roles in cancer. We created three cancer cell lines with p53 genetic status as the only variable and combined long-read RNA-seq and short-read RNA-seq to define TE and TE-derived transcripts’ regulatory dynamics. We identified in total 2,503 transcripts that used TE as potential promoters, among which, 141 to 210 were activated by p53. We found ERVs to be a main driver of potential promoters, followed by LINEs. Epigenomic profiling including chromatin accessibility and DNA methylation provided additional support for active promoter potential for p53 upregulated TE-derived transcripts. Short-term restoration of p53 partially recovered chronic p53-regulated TE-derived transcript profile but gain of function TP53 mutations, R175H and R273H, did not show evidence to act via TE network. Overall, we provide a controlled isogenic cancer cell line system with TP53 mutation status as the only genetic variable, deliver a high confidence TE and TE-derived transcript atlas and comprehensively identify active TE promoters that are direct and indirect targets of p53. The second part of my thesis inquires the relationship between p53 and TE under epigenetic therapy. Epigenetic therapy such as DNMTi and HDACi had passed clinical trials and been utilized in treating cancers. However the lack of their efficacy on other cancer types and certain patient populations remains puzzling. TEs are unleashed under epigenetic therapy due to the removal of epigenomic repression. We want to understand the regulation of p53 on TEs in the absence of epigenome restraints. Preliminary results showed that epigenetic therapy created a converging transcriptional landscape for p53 WT and KO cells. I observed an enriched upregulation of LTR12 subfamilies and THE1 subfamilies regardless of p53 activation, but specific copies of TE utilized by WT or KO are different. Future steps investigating the specific copies of TE along with the genes activated are necessary for understanding the different responses of p53 WT and KO cells to epigenetic therapy. Overall, my thesis furthers our understanding on TE regulation by p53. I hope this work can provide transcriptomic and epigenomic resources along with cell line systems that can help future researchers answer p53-centric questions in cancer. I also hope with the knowledge that we could fine tune the expression of p53-responsive TE-derived transcripts, we can better predict treatment response and facilitate transcriptomically-ready tumor states for p53-based therapies.

Committee Chair

Ting Wang

Committee Members

John Edwards; Luis Batista; Nancy Saccone; Samantha Morris; Yang Li

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-1-2026

Language

English (en)

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Genetics Commons

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