Dissertations and Theses (Open Access)
Author ORCID Identifier
0000-0003-2679-9829
Date of Graduation
5-2026
Document Type
Dissertation (PhD)
Program Affiliation
Quantitative Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Kunal Rai, PhD
Committee Member
George Calin, MD, PhD
Committee Member
Claudio Soto, PhD
Committee Member
Ken Chen, PhD
Committee Member
Nicholas Navin, PhD
Abstract
Nonmutational epigenomic reprogramming has emerged as a key hallmark of cancer that plays crucial roles in tumor evolution during its progression and response to therapy. However, the extent and nature of epigenomic reprogramming remains poorly understood. This dissertation examines how epigenetic regulation shapes cancer progression and response to immunotherapy. Working at the intersection of cancer biology and computational genomics, it develops analytical frameworks for characterizing chromatin structure and DNA methylation across diverse tumor contexts and uses these frameworks to address two complementary biological questions: how promoter-associated chromatin organization varies across cancer types, and how epigenetic perturbation modulates tumor immunogenicity in the clinical setting.
The dissertation addresses two primary questions: First, how is promoter chromatin structure (H3K4me3 breadth) organized across cancer samples, and what does this organization reveal about gene regulatory programs? Second, how does combining DNMT inhibition (azacytidine) with PD-1 checkpoint blockade alter epigenetic and transcriptional states in melanoma, and do these alterations predict therapeutic response?
Chapter 2 describes the development of a reproducible computational platform using Singularity containers and standardized workflow architecture on high-performance computing clusters. This infrastructure underpins all downstream analyses and addresses a common challenge in large-scale epigenomic research: ensuring that results are consistent and replicable across environments.
Chapter 3 introduces a promoter-centered strategy for integrating chromatin immunoprecipitation (ChIP-seq), DNA methylation (RRBS), and RNA-seq data. Signals from distinct assays are mapped to a shared promoter coordinate system, aggregated to pathway-level features, and analyzed using distribution-based methods — preserving biological structure that summary statistics obscure.
Chapter 4 characterizes variation in H3K4me3 domain breadth across cancer and normal samples at genome-wide scale. Key findings show that (1) promoter breadth is a structured, continuous variable that differs systematically between cancer and normal tissue; (2) broad-domain genes are enriched for housekeeping and tumor suppressor functions while narrow-domain genes are context-specific; (3) cancer samples exhibit increased chromatin heterogeneity; and (4) H3K4me3 breadth interacts with repressive H3K27me3 occupancy to define distinct promoter regulatory states.
Chapter 5 analyzes a melanoma clinical cohort treated with combined azacytidine and anti-PD-1 therapy. DNMT inhibition induces global DNA hypomethylation and reactivation of endogenous retroviruses (ERVs), triggering interferon-stimulated gene expression consistent with a viral mimicry mechanism. Responders and non-responders differ at baseline in methylation and transcriptional programs, with responders showing greater ERV reactivation and immune pathway activation suggesting that epigenetic priming of innate immune sensing may contribute to improved immunotherapy outcomes.
This work advances the understanding of cancer as a disease of dysregulated epigenetic organization, establishes generalizable computational methods for multi-omic integration, and provides translational evidence supporting the use of epigenetic priming strategies to enhance immunotherapy efficacy in solid tumors.
Recommended Citation
Schulz, Jonathan, "Understanding Epigenomic Landscapes in Cancer Progression and Immunotherapy Response" (2026). Dissertations and Theses (Open Access). 1546.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1546
Keywords
Cancer epigenomics, Epigenetic reprogramming, Promoter chromatin architecture, H3K4me3 breadth, Bivalent chromatin, DNA methylation, Multi-omic integration, Endogenous retroviruses, Viral mimicry, Immunotherapy response
Included in
Bioinformatics Commons, Cancer Biology Commons, Computational Biology Commons, Genomics Commons, Immunotherapy Commons