Muscle-invasive bladder cancers are 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 are 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 remain unknown. RESULT: We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. 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 transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. CONCLUSION: In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.
Genome biology. 2021 Apr 15*** epublish ***
Tejaswi Iyyanki, Baozhen Zhang, Qixuan Wang, Ye Hou, Qiushi Jin, Jie Xu, Hongbo Yang, Tingting Liu, Xiaotao Wang, Fan Song, Yu Luan, Hironobu Yamashita, Ruby Chien, Huijue Lyu, Lijun Zhang, Lu Wang, Joshua Warrick, Jay D Raman, Joshua J Meeks, David J DeGraff, Feng Yue
Department of Biochemistry and Molecular Biology, Penn State School of Medicine, Hershey, PA, USA., Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA., Department of Pathology and Laboratory Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA, USA., University of Illinois College of Medicine, Chicago, IL, USA., Department of Biochemistry and Molecular Biology, The Pennsylvania State University, College of Medicine, Hershey, PA, USA., Department of Surgery, Division of Urology, The Pennsylvania State University, College of Medicine, Hershey, PA, USA., Department of Urology, Feinberg School of Medicine and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA., Department of Pathology and Laboratory Medicine, The Pennsylvania State University, College of Medicine, Hershey, PA, USA. ., Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA. .