Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular, Cellular, and Developmental Biology

First Advisor

Dimitrova, Nadya

Abstract

Long noncoding RNAs (lncRNAs) play essential roles in both physiological processes and disease, including cancer. A growing body of evidence positions lncRNAs as key regulators and biomarkers in tumorigenesis. Mechanistically, functional lncRNAs can regulate gene expression through epigenetic and transcriptional pathways, acting either via scaffold-like motifs that recruit regulatory complexes or through their abundance, which contributes to RNA-mediated feedback that modulates transcriptional condensates. Within the Plasmacytoma variant translocation 1 (Pvt1) locus, two alternative transcription start site isoforms have been identified: the constitutively expressed Pvt1a and the stress-inducible Pvt1b. While the precise functions of Pvt1a were not well understood, previous studies proposed that Pvt1b, a p53-dependent isoform, represses the transcription of the neighboring proto-oncogene Myc under genotoxic and oncogenic stress conditions. My work contributed to revealing that Pvt1a and Pvt1b act additively to locally restrict Myc expression during both homeostasis and in response to cellular stress. We found that Pvt1 transcripts fine-tune Myc transcriptional bursting locally in a dose-dependent manner. Disrupting Pvt1 transcription prolonged Myc burst duration, increased Myc expression, and accelerated tumor growth in mouse models of lung cancer. Using long-read sequencing, we uncovered substantial isoform diversity within the Pvt1 locus, which dynamically shifts in response to stress, arguing against specialized isoform functions. Furthermore, genetic dissection of endogenous Pvt1 exons identified specific RNA (or potentially DNA) elements, particularly exons 2 and 10, that appeared to influence MYC protein levels independently of transcription, suggesting that the Pvt1 locus may contribute to multiple mechanisms of Myc regulation. Collectively, my work has conceptually advanced our understanding of lncRNA function across multiple layers of gene regulation and has demonstrated how cis-acting lncRNAs fine-tune transcriptional dynamics and influence cancer biology. Importantly, our studies highlight the dynamic role of lncRNAs in transcriptional regulation and point to the therapeutic potential of targeting lncRNAs to modulate MYC activity in cancer.

Download

Share

COinS