Dissertation
PRMT5-mediated epigenetic regulation in epithelial development and oncogenesis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007844
Abstract
During development, the initially single-layered surface ectoderm undergoes precisely coordinated proliferation, differentiation, and adhesion to form the stratified epidermis and oral mucosa. Disruptions in these processes can cause congenital anomalies affecting the epidermis or oral epithelium, while reactivation of these pathways in adults can trigger cutaneous or oral carcinomas. Protein Arginine Methyltransferase 5 (PRMT5)—an enzyme that methylates arginine residues in histone and other proteins—maintains stem-cell quiescence in both development and cancer, leading us to hypothesize that PRMT5 preserves the progenitor status of oral and surface keratinocytes in vivo. To evaluate this hypothesis, we generated conditional knockout (cKO) mice lacking Prmt5 in early ectoderm, impacting the epidermis and oral mucosa. While Prmt5 cKOs displayed severe epidermal defects, compromised barrier function, and reduced postnatal viability, they exhibited no overt oral mucosa defect. Histological analyses revealed significant defects in epidermal stratification, without alterations in apoptosis or proliferation. Single-cell RNA and ATAC-seq analyses identified an atypical population of basal keratinocyte-like cells in Prmt5 cKOs, that exhibited a senescence-like program, characterized by increased expression of Cdkn1a (p21), elevated senescence-associated secretory phenotype (SASP) molecules (Igfbp2), and decreased developmental transcription factor (Trp63) expression. Comparison of these developmentally dysregulated genes with those dysregulated in a Prmt5-deficient oral squamous cell carcinoma (OSCC) cell line revealed significant overlap in molecular programs, including senescence induction. These findings demonstrate that Prmt5 knockout functions through senescence-based pathways in development and cancer, with epidermal loss causing severe epidermal defects in development but potentially serving as a therapeutic target in oral carcinoma.
Details
- Title: Subtitle
- PRMT5-mediated epigenetic regulation in epithelial development and oncogenesis
- Creators
- Nicole Recka
- Contributors
- Eric Van Otterloo (Advisor)Martine Dunnwald (Committee Member)Andrean Simons-Burnett (Committee Member)Bin He (Committee Member)C. Andrew Frank (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007844
- Publisher
- University of Iowa
- Number of pages
- xviii, 255 pages
- Copyright
- Copyright 2025 Nicole Recka
- Language
- English
- Date submitted
- 04/24/2025
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 216-255).
- Public Abstract (ETD)
- Epithelial cells have the unique ability to tightly pack together and form essential barriers within our body. When these cells accumulate mutations, they can begin to grow uncontrollably and spread to other tissues, resulting in carcinoma. Research has identified Protein Arginine Methyl Transferase 5 (PRMT5) as an important factor in the formation and progression of many carcinomas. While drugs targeting PRMT5 have entered clinical trials, these treatments have shown limited effectiveness, highlighting the need for investigation into how PRMT5 functions at a molecular level. Developmental biologists have identified that many cancers reactivate processes that are normally beneficial during development, such as rapid cell growth and movement, which become harmful when hijacked by cancer cells. Therefore, to gain deeper insights into PRMT5’s role in cancer, we must first understand its function during normal epithelial development. Our research using mice genetically engineered to lack PRMT5 in oral and skin epithelial cells shows that these animals do not survive after birth and develop abnormal skin and unusual cell structure. Sophisticated single-cell sequencing of this defective epidermis revealed a group of cells that show increased levels of senescence. Senescence can be thought of as a cellular “standby mode” where cells neither function normally nor die, but instead enter a suspended state. Studies have linked senescence to treatment resistance of cancer cells, providing insight into why PRMT5 inhibitors have limited clinical effects. The knowledge gained from this study may inform the development of combination therapies that will increase the therapeutic response to PRMT5 inhibitors.
- Academic Unit
- Craniofacial Anomalies Research Center; Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984831230602771
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