Chromatin reorganization and differential transcription factor binding underpins lineage switching. (A) DNase I hypersensitive site sequencing identified 13 619 sites with a log2-fold reduction and 12 203 sites with a log2-fold increase after lineage switching to AML. Relative peak heights in the AML sample were plotted against those of the ALL sample. (B) A University of California, Santa Cruz (UCSC) Genome Browser screenshot displaying differential expression at lineage-specific loci (red tracks) accompanied by altered DNase I hypersensitivity (black tracks) proximal to the transcriptional start site (TSS) of CD33. (C) UCSC Genome Browser screenshot for CD19 zoomed in on an ALL-associated DHS with EBF occupation as indicated by high-resolution DHS-seq and Wellington analysis. FP, footprint. (D) Heat maps showing distal DHS regions specific for AML relapse on a genomic scale. Red and green indicate excess of positive and negative strand cuts, respectively, per nucleotide position. Sites are sorted from top to bottom in order of decreasing footprint occupancy score. (E) De novo motif discovery in distal DHSs unique to AML relapse as compared with ALL relapse, as shown in panel D. (F) EBF1 and C/EBP binding motifs demonstrate differential motif density in presentation ALL and relapsed AML. DHS, DNase-hypersensitive site.
