Epigenomic profiling of diseased 3aKO-140 HSPCs. (A) Differentially methylated regions in 4 genotypes from enhanced RRBS data. The 3 types of DMRs are 3aKO-140 Hyper, WT-140 Hyper, and 3aKO Hypo regions. (B) The overlap between the 3 DMRs in panel A. (C) Gene Ontology term analysis of genes associated with the 3 DMRs. (D) The overlap between the 3aKO-140 Hyper region and the HSC DNA methylation canyon. The P value was calculated by genomic distribution test. (E) KEGG pathway analysis of genes associated with enhanced H3K27ac signal in 3aKO-140 HSPC relative to WT. (F) The overlap of altered enhancer regions in 3aKO-140 HSPCs vs WT MEPs with annotated megakaryocyte (MkP) enhancer.⁵⁰  (G) The detail of the Gata2 enhancer region, where DNA methylation is low in 3aKO-140 HSPCs. (H-I) Heatmaps showing (H) the whole-genome differentially methylated cytosines (DMCs) and (I) DMCs overlapping with normal CD34⁺ enhancers in AML patients bearing only the DNMT3A mutation, only the IDH1/2 mutation, or both the DNMT3A and IDH1/2 mutations. Patient 450K DNA methylation array data are from The Cancer Genome Atlas. Enhancer regions are defined as H3K27ac-enriched regions from the Encyclopedia of DNA Elements data on human CD34⁺ bone marrow cells. In the 2 highest bars above the map, black indicates the patient carries a mutation in the labeled gene and gray indicates the patient does not carry a mutation. In the colored bar immediately above the heatmap, blue marks the cluster of patients enriched in DNMT3A mutations; orange marks the patients having both DNMT3A and IDH1/2 mutations; and purple marks the patients enriched in IDH1/2 mutations.