Figure 2. Differential epigenetic priming of Kras-mutant cells.

(A) Force-directed layout (FDL) of all Kras-mutant scRNA-seq profiles (K1–K6, n = 11 mice). Cells colored by stage as in Fig. 1A. Stars highlight ‘apex’ states inferred by CellRank (39) (see Fig. S3B). (B) Principal component analysis (PCA) of bulk ATAC-seq profiles from pancreatic epithelial cells. Each point shows the position of a single biological replicate (individual mouse), colored by stage as in (A). Arrows indicate a transition upon injury and Kras mutation (N1-N2, K1-K2; green arrow) and a divergence between benign neoplastic (K3-K4; pink arrow) and malignant (K5-K6; purple arrow) stages. (C) Left: Chromatin accessibility along progression. Subsets of differentially accessible ATAC-seq peaks (rows) are organized into three modules by clustering (27); bulk ATAC-seq replicates (columns) are ordered and colored by stage as in (A). Peaks organize into distinct accessibility patterns, denoted as chromatin modules (27). Right: Expression of genes corresponding to chromatin accessibility modules in pre-neoplastic cells (K1, K2). FDL map as in (A), colored by module expression score computed by z-scoring each cell to emphasize dominant gene programs per cell, and averaging genes nearest to module peaks. Color (expression scores) are scaled between the 40^th and 90^th percentiles. (D) Probability of classifying pre-neoplastic cells (K1, K2) as more similar to benign neoplastic (K3-K4) or malignant (K5-K6) scRNA-seq profiles, based on expression similarity. Sampled cells (rows) are ordered from highest benign fate probability (top) to highest malignant fate probability (bottom); bars represent probability of classification from 0 to 1 to K3, K4, K5, or K6 labels, colored as in (A). A fraction of cells exhibit composite states with probability for both fates.