Analyses of Internal CRISPR Screen and RNA-Seq data, and Publicly Available Genomic Datasets to Study the Roles of Epigenetics in Cancer Biology.

Author

Christiane M. Morecock, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/8WG7-C354

Author ORCID Identifier

0000-0003-4956-7991

Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Human Genetics

First Advisor

Joseph Landry, Ph.D.

Abstract

Epigenetic modifications feature prominently in the biological changes necessary to promote tumor growth, invasion, and metastases. Lessons learned from clinical trials of first-generation epigenetic treatments for cancer have demonstrated a need for biomarker-driven clinical strategies, more highly specific drug targets to limit toxicity in humans, and the ability to use multiple drug targets in combination to increase efficacy of current cancer treatments in solid tumors. Future investigation of epigenetic targets would need to incorporate these lessons to ensure responsible research. However, attempting to address these needs by serialized laboratory experiments alone would be time and resource intensive. We demonstrate data science techniques that can be used to streamline the search for potential epigenetic targets for cancer therapies that should be prioritized for molecular follow-up. First, we use robust, publicly available databases to gain insight on Nucleosome Remodeling Factor (NURF), a chromatin remodeling complex that has shown to contribute to cancer cell biology in model organisms. In particular, we investigate the efficacy of inhibiting BPTF, a unique and essential subunit of NURF that has been reported to be a highly druggable potential target of the NURF complex. Then, we use internal RNA-sequencing data to gain insight about the anti-tumor mechanism of combination Guadecitabine and BPTF inhibition therapy. Finally, we use a CRISPR knock out (CRISPR_KO) screen of 450 epigenetic regulators to identify novel epigenetic targets to prevent proliferative recovery of tumor cells. Study findings identify future directions for molecular studies for novel epigenetic targets in cancer therapy, including BPTF.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-10-2022