Fig. 3
CLL-specific DNA methylation differences result from aberrant transcription factor programming. a Enrichment of chromatin states in sequences representing CLL-specific DNA methylation. Chromatin states were defined using the 15-state ChromHMM model from immortalized B cells [36] for CLL-specific methylation sites of the classes A–D. The enrichment in category “Repetitive/CNV” represents the averaged enrichment value of ChromHMM states called “Repetitive/CNV.” Log2 fold change (log2 FC) was calculated using all 450K probes as a background. b Enrichment of super-enhancers (SE) in sequences representing CLL-specific DNA methylation. SE were defined as either being gained in CLLs (gained) or consensus between CLLs and B cells (stable). Fold change (FC) was calculated using all 450K probes as a background. c ATAC-seq read density (normalized read counts × 10− 3) at CLL-specific CpG sites (± 1 kb) for categories of classes A, B, C, and D. CLL samples (n = 18) are represented in orange, normal CD19+ B cells (n = 3) in green. Transcription factor enrichment analysis using ENCODE ChIP-seq peaks from the B-cell lymphoblastoid cell line, GM12878. Displayed are –log10 (p values) resulting from Fisher’s exact test with false discovery rate correction. e Transcription factor motif enrichment analysis using HOMER. The top 10 most enriched TF motifs for each class are displayed. The colors represent –log10(p values) derived from a cumulative binomial distribution function as implemented in HOMER. f ATAC-seq & ChIP-seq read density (normalized read counts × 10− 3) and DNA methylation profiles at class D CpGs co-locating with CTCF motifs (23 CpGs) (± 1 kb). CLL samples (n = 7 CTCF ChIP-seq, n = 18 ATAC-seq) are represented in orange, normal CD19+ B cells (n = 4 CTCF ChIP-seq, n = 3 ATAC-seq) in green. g Locus plots of exemplary genes associated with CTCF/class D events. Locus plots include data from CTCF ChIP-seq on normal B cells (red) and CLL (blue); ATAC-seq on normal B cells (green) and CLL (purple); RNA-seq on NBC (light green), hiMBC (dark green) and CLL (orange). The class D CpGs are annotated in red