Fig. 6: ERG drives a unique chromatin state in IM cells featuring STAT3 and other TFs.
From: ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L
a, UMAP of scATAC-seq showing epithelial cell clusters assigned to each genotype (n = 16,006 total number of epithelial cells). Dorsal–lateral lobes from indicated mice at different ages (4 weeks, 3 months and 6 months) were pooled together and analyzed (Extended Data Fig. 9a). b, Single-cell ChromVar enrichment of ETS family (ERG, ETS, ETV, FLI) motifs. c, Violin plots showing cells grouped by cell type on the x axis and arranged by pseudotime on the y axis. d, Heatmap of TF motifs enriched per cell type. Hypergeometric tests were performed for each motif’s accessibility within each cell type compared with all other cell types. Motifs with an FDR-adjusted P < 10−20 are shown. Major cell-type-specific motif families are highlighted. e, Trajectories of three EPC-IM-enriched motifs. f, Co-accessible ChromVar Z scores of indicated motifs in EPC-IM cells with or without ETS factors. Boxplots are centered at the median value and the lower and upper hinges correspond to the interquartile range (IQR) at the 25th and 75th percentiles, respectively. The lower and upper whiskers extend from the hinge to the smallest or largest value at most 1.5 × IQR of the hinge, respectively. FDR-adjusted P values above the violin were calculated with one-sided Wilcoxon rank sum test using ChromVar Z scores of peaks with co-occurring motifs versus exclusively one motif. g, Left: schematic showing individual genes perturbed in fresh tumor-derived organoids (EPC) before orthotopic transplantation. Whole prostates of EPC mice (3–9 months) were pooled, edited and shortly expanded as organoids before orthotopic transplantation into host dorsal lobes. Right: normalized weight of injected lobes from indicated orthografts (left to right: n = 26, 4, 4, 6, 6, 12, 6, 14 grafts). TFs are categorized based on motif accessibility enrichment in indicated clusters. h, Histological analysis on orthografts collected at the 1-month time point (8 grafts per group). Tumor areas were quantified based on ERG/Stat3/pAkt status as highlighted in yellow dashed lines. Arrows in the EPC;sgStat3 group highlight ERG+ cells that retain Stat3 expression. Scale bars, 250 µm. Data represent mean ± s.d.; one-way ANOVA with Dunnett posttest (g); one-way ANOVA with Tukey posttest (h).
