Fig. 4: Gene Regulatory Network for PAH based on TF-enhancer-gene links.

a Schematic representation of the gene regulatory network (GRN) approach. b Fraction of consistent interactions defined as regulatory interactions where the TF activity varies in the same direction as the H3K27ac signal at the putative target peak. The consistency increased considerably around the 20% FDR threshold (see Methods). c Percentage of regulatory interactions mediated by enhancers that are connected to the nearest transcription start site (TSS; blue, n = 1289) vs other TSS (orange, n = 6153). d GRN in PAH. Nodes represent TFs (square) and target genes (circle) that are within chromatin regulatory domains (CRDs). TFs more active in PAH (red), TFs more active in controls (blue), target genes more active in PAH (orange) and target genes more active in control (green). The color of the edges represents a positive (green) and negative (red) correlation for TF expression and H3K27ac signal at the promoter of the target gene. TFs with more than 100 connections were removed to improve clarity of the network visualization. The network is provided in Supplementary Data 5. e Ranked TFs by their number of interactions in the PAH genetic regulatory network. f Ranked target genes by their number of interactions in the PAH genetic regulatory network, to make clear the plot only the top 100 target genes are represented. g Detailed sub-network of the PAH-GRN of known genes associated with PAH (large nodes) and their first interactors (small nodes).