Fig. 4

DMRs in iPSCs reveal tissue-persistent epimutation hotspots at developmentally and laminopathy relevant genes. a Hierarchical clustering of iPSC samples by genome-wide DNA methylation. Colors represent family groups. b Venn diagram showing the number of DMRs captured by group for both hypermethylated and hypomethylated DMRs. Orange regions denote “Shared DMRs,” green regions denote “Family A-specific DMRs,” and purple regions denote “Family C-specific DMRs.” c Number of DMRs captured within fibroblast and iPSC samples for each grouping for hypermethylated and hypomethylated DMRs. d Log odds ratio of a CpG falling within both a DMR group and a given histone modification in iPSC and fibroblast. e Example of Family C DMR proximity in both cell types. Top, Genome browser track displaying DMRs based on mean methylation differences (patient minus control) in fibroblasts and iPSCs. Middle, Methylation levels for patient and control samples for each cell type. Bottom, Depiction of RefSeq gene annotation. f Number of either differentially methylated CpGs or randomly sampled CpGs in iPSC that fell within a range of genomic distances from their closest neighboring fibroblast CpG in the same family; Fisher’s exact test: *p ≤ 0.05; ***p ≤ 0.001; ****p ≤ 0.0001 g Diagram depicting the number of genes associated with DMRs falling within one of eight categories of DMR methylation patterns in fibroblast and iPSCs. h Table highlighting laminopathy-related disease ontologies enriched in DMRs grouped by fibroblast and iPSC DMR state (hyper- or hypomethylated). Heatmap reports the degree of statistical significance for disease enrichment. i Protein–protein interaction (PPI) network of 28 genes associated with Family C-specific DMRs (hypermethylated in fibroblasts and hypomethylated in iPSCs) and either LMNA-related dilated cardiomyopathy (DCM), congenital abnormality, or both. Pathway enrichment and disease association are denoted by color and shape, respectively. Orange node borders indicate that the gene is differentially expressed in cardiac tissue (cardiac DEG)