Fig. 2

Hypermethylated and hypomethylated DMRs localize at distal regulatory features and transcriptionally repressed chromatin in fibroblasts. a Hierarchical clustering of all fibroblast samples by genome-wide DNA methylation. Colors represent family groupings. b Venn diagrams 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 Top, Hierarchical clustering of all samples by shared DMR methylation. Bottom, Heatmap of average CpG (≥ 5 × depth) methylation percentage across shared DMRs for each individual sample. Genes associated with heart and skeletal system development are shown next to the associated DMR. d Density plot of mean methylation difference (patient minus control) within DMRs by group. Overall Kruskal–Wallis test p-value is displayed. e Line plot of log odds ratio of the likelihood of CpGs to fall within a hypermethylated (“Hyper”) or hypomethylated (“Hypo”) DMR and a given range of genomic distance away from a gene’s TSS. Open circles designate log odd ratios that were non-significant (p-value > 0.05) by Fisher’s exact test. f Heatmap showing the log odds ratio of a CpG falling within both a DMR group and a given histone modification. g Heatmap showing the log odds ratio of a CpG falling within both a DMR group and one of 25 ChromHMM annotated genomic regions. h Table highlighting TFBS motifs enriched in shared, Family A, and Family C DMRs, grouped by TF-related categories. Heatmap reports the degree of statistical significance for TFBS motif enrichment. Results were categorized as hypomethylated (red) or hypermethylated (blue) according to the type of DMR associated with a particular TFBS motif