DNA methylation changes in Dnmt3a-null driven malignancies. (A) Distribution of absolute DNA methylation levels in all experiments for genomic regions subject to differential methylation in MDS, AML, and/or T-ALL mice. The width of the y-axis indicates the frequency with which the value is observed. (B) The top 6 classes of DNA methylation changes (relative to control samples) across the diseases are shown. Hypermethylation in T-ALL is the most frequent, and shared hypomethylation between MDS and AML is the second most frequent. (C) The methylation levels of DMRs in 1 or more diseases were analyzed by hierarchical clustering using a Jensen-Shannon distance metric of methylation specificity. (D) Pie chart showing the proportion of DMRs in T-ALL mice by gee association. Left chart summarizes region coverage of intergenic, introns, exons, and promoters. Right chart summarizes DMRs by the same categories. (E) Chromatin and transcriptional regulator enrichment analysis of MDS, AML, and T-ALL DMRs. Enrichment of DMRs in peaks or binding sites curated in publicly available mouse functional genomics data sets for the indicated factors and cell/tissue lineages was quantified using odds ratios and P values (Benjamini-Hochberg testing correction) determined by Fisher’s exact test. Dot sizes are proportionate to the odds ratio. Color intensity represents the negative-log Benjamini-Hochberg–corrected P value. Nonsignificant results are in gray. (F) T-ALL hypermethylation recapitulates functions and ontologies of human leukemia. Potential cis-regulatory functions of promoter-proximal (10 kb up to 1 kb downstream of transcriptional start sites) hypermethylated DMRs in T-ALL were predicted with GREAT 2.0. All enriched terms have a multiple testing corrected q < 0.005. CGI, CpG islands; LSK, Lin-Sca-1+c-Kit+; NS, nonsignificant; TALL, T-ALL; THY, thymus; UMR, undermethylated regions.