(a) Clustered correlation heatmap of perturbations. Gene expression profiles for genes with mean UMI count > 0.25 in the entire population were z-normalized to expression values in cells with negative control sgRNAs and then averaged for populations with the same sgRNA. Crosswise Pearson correlations of all averaged transcriptomes were clustered by the Ward variance minimization algorithm implemented in scipy. Cell numbers for each perturbation are listed in Supplementary Table 14. (b) UMAP projection, distribution of cells with indicated sgRNAs, target gene expression (rolling mean over 50 cells), and magnitudes of transcriptional changes for all differentially expressed genes and selected ISR regulon genes (rolling mean over 50 cells) for cells with knockdown of ATP5E or control cells. n = 2,781 cells total (negative control: 2,084 cells; ATP5E (0.070): 101 cells; ATP5E (0.554) 136 cells; ATP5E (0.914): 137 cells; ATP5E (1.000) 175 cells; ATP5E (1.185) 148 cells). See Methods for details.