Epigenomic regulation and 3D Genome Structure in Muscle-Invasive Bladder Cancers
Open Access
- Author:
- Iyyanki, Sriranga
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 18, 2020
- Committee Members:
- Feng Yue, Dissertation Advisor/Co-Advisor
James Riley Broach, Committee Chair/Co-Chair
David James Degraff, Committee Member
Hong-Gang Wang, Committee Member
Edward Joseph Gunther, Outside Member
Zhonghua Gao, Committee Member
Ralph Lauren Keil, Program Head/Chair
Feng Yue, Committee Chair/Co-Chair - Keywords:
- Bladder Cancer
Epigenetics
Epigenomics
Genomics
Transcription Factor
Molecular Subtypes - Abstract:
- Molecular alterations in the form of gene mutations, gene duplications or deletions, gene expressions, and epigenetic DNA methylation of cis-regulatory promoters have been used to describe clinical features of bladder cancers. This had led to a new paradigm of developing and deploying precision medicine treatment strategies with assisted molecular biomarkers. Specifically, aggressive muscle-invasive bladder cancers have been shown to be characterized by their distinct expression of luminal and basal genes that are associated with key clinical features such as disease progression and overall survival. Transcription factors such as FOXA1, GATA3, and PPARγ have been shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63 and STAT3 are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms for subtype-specific regulation in bladder cancers remains unknown. This dissertation used a genome-wide and multi-Omics approach to determine the transcriptome, epigenetic promoter and enhancer landscapes and 3D genome structures to describe bladder cancer subtypes and further identifying novel epigenetic mechanisms for the subtype regulation. The first study constructed a multi-Omics resource for studying the bladder cancer epigenome. Integrative analysis of transcriptome and epigenome landscapes of bladder cancer subtypes showed that luminal and basal bladder cancers show coordinated regulation of gene expression with promoter/enhancer histone marks. Open chromatin sites located within the regulatory regions show that the TF repertoire may drive subtype-specific promoters and enhancers in bladder cancers. We also showed that the subtype-specific epigenomic and transcriptome profiling could be used to perform tumor deconvolution to estimate the subtypes in mixed cell populations. Finally, we show distinct 3D genome regulations in bladder cancer subtypes forming distal looping between enhancers and promoters. In our subsequent study, we demonstrated the utility of our resource by exploring subtype-specific TF regulation mechanisms. First, we showed that luminal promoter and enhancer regulatory regions are bound by their luminal-specific TFs FOXA1 and GATA3. Then, we identified a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other luminal-specific genes (including FOXA1, GATA3, and PPARγ) and influences cancer cell proliferation and migration. In summary, the studies conducted in this dissertation is a comprehensive multi-Omics resource for epigenome and 3D genome for studying molecular subtypes of bladder cancers. Additionally, we demonstrate the utility of our resource through the identification of novel clinically relevant targets such as the circadian TF NPAS2 for potential use in clinical settings.