Abstract
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.ResultWe 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.ConclusionIn 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.
Highlights
Urinary bladder cancers (BLCA) are the second most commonly diagnosed urologic malignancy in the USA, with over 81,400 total new cases diagnosed in 2019 [1, 2]
We previously reported that FOXA1 and GATA3 cooperate with PPARG activation to drive transdifferentiation of basal BLCA cells to luminal subtype [8]
Comprehensive epigenomic profiling in both BLCA lines and primary tumors In this project, we performed RNA-Seq, ChIP-Seq for Histone 3 lysine 27 acetylation (H3K27ac), Assay for Transposase-Accessible Chromatin using sequencing (ATACSeq), and genome-wide chromatin confirmation capture experiments (Hi-C) on 4 bladder cancer cell lines (Fig. 1a), two of which (RT4 and SW780) were previously annotated as luminal and the two others (SCABER and HT1376) that were characterized as basal [8, 25]
Summary
Urinary bladder cancers (BLCA) are the second most commonly diagnosed urologic malignancy in the USA, with over 81,400 total new cases diagnosed in 2019 [1, 2]. Recent studies have identified both luminal (FOXA1, GATA3, and PPARG [8]) and basal (TP63 [9,10,11,12], STAT3 [4, 13,14,15], TFAP2A, and TFAP2C [16]) -specific transcription factors (TFs) with functional roles in BLCA. We previously reported that FOXA1 and GATA3 cooperate with PPARG activation to drive transdifferentiation of basal BLCA cells to luminal subtype [8]. This observation is in agreement with the role of these factors in maintaining urothelial cell differentiation [17, 18] and supports a role for inactivation of FOXA1, GATA3, and/or PPARG during BLCA progression to a basal subtype. Specific TFs play a key role in subtype specification
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