Extended Data Fig. 10: FOXA1-mediated enhancer reprogramming confers tumour subtype plasticity of urothelial carcinomas through a FOXA1–BMP–hedgehog signalling feedback axis between the epithelial tumour and stroma.

a, c, Heat maps of ATAC-seq, H3K27ac ChIP–seq, and RNA-seq for GAIN/LOSS regions/genes from indicated samples. Hierarchical clustering was performed on ATAC-seq and H3K27ac ChIP–seq. b, d, GSEA of indicated samples to assess differential enrichment of GAIN genes (left) and signature genes for cell differentiation (right). NES, normalized enrichment score. Nominal p value is shown e, f, Relative expression of FOXA1 in basal tumour organoid B1 (e) and B2 (f), treated with BMP4, BMP5, or BMP4 and BMP5 together. Data are mean ± s.e.m. g, h, Representative ATAC-seq, H3K27ac ChIP–seq, and FOXA1 ChIP–seq profiles of the regions at IRX2 loci in the indicated samples. i, j, Molecular subtypes of indicated samples were analysed using the BASE47 together with MDACC classifiers. Heat maps show the normalized gene expression profile organized by the luminal and basal classifier genes. k, l, Heat map representation of unsupervised hierarchical clustering from ATAC-seq (k) or H3K27ac ChIP–seq (l) data for tumour assembloids in each experiment summarized in Extended Data Fig. 9a–d. Samples were clustered based on the Spearman correlation coefficient with single linkage. m, Principal components analysis from RNA-seq data for tumour assembloids in each experiment summarized in Extended Data Fig. 9a–d. n, Representation of motifs enriched at the regions with increased chromatin accessibility/H3K27ac signals in basal. o, Top 5 enriched de novo motifs and transcription factors with best matched binding motifs in regions with increased chromatin accessibility/H3K27ac signals in basal. The most enriched motif shows high similarity with AP-1 transcription factor binding motifs. For details on statistics, sample sizes (n), and numbers of replications, see ‘Statistics and reproducibility’ (Methods).

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