Abstract 2189: Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer

Abstract

Abstract Urinary bladder cancers (BLCA) are commonly diagnosed urologic malignancy in the United States. Muscle invasive BLCA is a morbid and expensive disease to treat, thus increased molecular understanding is necessary. BLCA has recently been characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARg have been shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remains unknown. Here, we determined the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles (FOXA1 and GATA3) in luminal and basal subtypes of bladder cancers. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct TF binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identified a novel clinically relevant transcriptional factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. In summary, our work identifies a subtype-specific epigenomic and 3D genome structure in urinary bladder cancers and suggests a novel link between the circadian TF NPAS2 and a clinical bladder cancer subtype. Citation Format: Tejaswi Tejaswi, Baozhen Zhang, Qixuan Wang, Ye Hou, Qiushi Jin, Jie Xu, Hongbo Yang, Tingting Liu, David J. DeGraff, Feng Yue. Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2189.