a, Number of reads (left) and expression of IGH genes (right) in index-sorted B cells, validating our index-sorting strategy (CD27−IgM+IgD+++IgG− (NBC, n = 24 cells), CD27−IgM+IgD+IgG− (loMBC, n = 24 cells), CD27+IgM+IgD++IgG− (intMBC, n = 24 cells), and CD27+IgG+ (hiMBC, n = 23 cells)). Violin plots represent kernel density estimation showing the distribution shape of the data. b, Proportion of cells with gene expression (read count > 0) and exhibiting above-threshold DNAme. Data are mean ± s.e.m. across all genes with sufficient RNA (expression seen in >5 cells) and DNAme (>5 CpGs per promoter) information across the three samples (n = 1,816 genes). c, Transcriptional entropy across cells (see Methods) showing higher transcriptome entropy in CLL cells (CLL03, n = 94; CLL04, n = 92) than in healthy donor B cells (B04, n = 84) across various downsampling regimes (range 5,000–100,000; step-size of 1,000). Data are mean ± s.e.m. d, e, Single-cell transcriptional entropy (d) and epimutation rate (e) between normal CD27− B (NBC and loMBC) and CD27+ B (intMBC and hiMBC) cells. f, Left, distribution of the Spearman’s rho between expression and promoter DNAme rate (n = 3,094 genes with sufficient RNA (expression seen in >5 cells) and DNAme (>5 CpGs per promoter) information) in CLL04. The observed Spearman’s rho values were compared to values obtained by randomly permuting cell labels for the methylation values (see Methods). Right, heat maps of Spearman’s rank-order correlation for representative genes with positive or negative single-cell expression-methylation correlation. Scale bar represents promoter methylation and RNA read counts scaled by maximal value. g, As in f for individual normal B cells (n = 5,729 genes; n = 16 permutations; see Methods for details). h, As in g for CLL03 (n = 2,699 genes; n = 16 permutations). i, As in g for CLL04 (n = 3,094 genes; n = 16 permutations). j, Absolute change in Spearman’s rho when comparing matched versus scrambled DNAme and RNA single-cell data in CLL (CLL03 and CLL04) and normal B (B04) cells. From the pool of genes used in g–i, only overlapping genes (n = 951) across the three samples were used in the comparison. k, As in f for individual normal B cells (n = 2,500 most variable genes with sufficient RNA (expression seen in >5 cells) and DNAme (>5 CpGs per promoter) information; n = 16 permutations; see Methods for details). l, As in k for CLL03. m, As in k for CLL04. n, Absolute change in Spearman’s rho when comparing matched versus scrambled DNAme and RNA single-cell data in CLL (CLL03 and CLL04) and normal B (B04) cells. From the pool of genes used in k–m, only overlapping genes (n = 459) across the three samples were used in the comparison. o, Hydroxymethylation (5hmC) level at genes with positive correlation between expression and promoter DNA methylation (top correlated 10% of genes) compared with negatively correlated genes (top anti-correlated 10% of genes) in both normal B (B04; n = 336 and 330 genes, respectively) and CLL (CLL03 (n = 290 and 278 genes, respectively); CLL04 (n = 320 and 314 genes, respectively)) cells. Error bars represent 95% confidence interval. Published 5hmC data were used for the analysis19. Box plots are as defined in Fig. 1. P values were determined by two-sided Kolmogorov–Smirnov test (f–i, k–m), two-sided Wilcoxon signed-rank test (j, n) or two-sided Welch’s t-test (o).