Abstract

Transposable elements (TEs) contribute to nearly half of the human genome yet have been overlooked in genomic medicines due to the stereotypic impression as “junk DNA” and technical challenges. However, studies in the last two decades demonstrated that dysregulation of the epigenome in cancer cells resurrects the cis-regulatory functions of TEs, including the promoter activities. The tumor-specific TE activation events along with the resulting tumor-specific RNA and protein molecules, provide a potential “gold mine” for identifying tumor-specific therapeutic targets for cancer treatments, including immunotherapy. Here, I present a series of works to investigate the potential of providing actionable, pan-cancer, and inducible immunotherapy targets by leveraging tumor-specific activation of TEs. The first three works validated the universal expression of TE-derived transcripts, and the presentation of the resulting antigens and membrane proteins. More importantly, we demonstrated that these TE-derived proteins are inducible, and the TE-derived antigens can stimulate immune-responses. The fourth work in my thesis focused on investigating the regulatory mechanisms of TP53 on TEs. We demonstrated that despite having an overall repressive effect on TEs, TP53 represses and activates different subsets of TEs in the meantime depending on factors including the presence and the density of TP53 binding motifs in TE sequences. The fifth work in my thesis, as a review, summarized and discussed recent advancements in leveraging TEs for cancer treatments, and technical hurdles for analyzing TEs in genomic medicines. The sixth and the last work in my thesis switched the topic and focused on discussing the role of TEs in maintaining and reshaping the chromatin architecture of the mammalian genomes.

Committee Chair

Ting Wang

Committee Members

Li Ding; Malachi Griffith; Robert Schreiber; William Gillanders

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

5-8-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-1414-1256

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