Date of Award

12-2022

Document Type

Dissertation

Degree Name

Ph.D.

Department

Basic Medical Sciences

Committee Chair

Glen M. Borchert, Ph.D.

Abstract

The human genome is rife with regulatory elements that control whether genes are expressed or silenced. While regulatory elements such as epigenomic modifications, transcription factors, promoters, and enhancers are well established, there still remain regulatory elements that are poorly characterized or even undiscovered. In recent years, noncoding RNAs derived from small nucleolar RNAs were identified and linked to gene regulation in a variety of human cancers. Adding to the growing understanding of these sdRNAs, we performed a computational analysis of castration-resistant prostate cancer patient data and identified 38 sdRNAs as significantly overexpressed in CRPC. Two of these, sdRNA-D19B and sdRNA-A24, were found to regulate the expression of tumor suppressor genes CD44 and CDK12 respectively, thus functioning as oncogenic ncRNAs in CRPC. At the level of chromatin conformation, we developed a custom Hi-C analysis pipeline to characterize the interactome of long guanine quadruplex regions. The pipeline successfully identified LG4 contacts with local genes and regulatory elements, indicating that LG4s form topologically associated domains and likely function as a novel mechanism of gene regulation and genomic organization. Taken together, the work presented adds 38 sdRNAs and an entirely new level of gene regulation via LG4 TADs to the growing catalogue of regulators of human gene expression.

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