Fig. 5

Chromatin accessibility change drives differential gene expression and dedifferentiation in FAD mutant hiPSC-derived neurons. A Differential ATAC-seq peaks with corresponding differential gene expression change in APP^V717I, PSEN1^A79V, and PSEN2.^N141I hiPSC-derived neurons relative to NDC; right, annotation (promoter, PEREGRINE enhancer, or distal/intergenic) and direction of differential ATAC-seq peak change. B CONfident efFECT size (confect) of differential chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) for significant genes (by ATAC-seq) using topconfects. C quasi-proportional Venn diagram overlap of genes with significant differential accessibility and gene expression change between the FAD mutations. D Union of all genes with significant differential accessibility and gene expression in three FAD mutations; left, peak-centered ATAC-seq coverage in all four conditions; right, differential confect score for ATAC-seq and RNA-seq for each gene (relative to NDC), with corresponding z-score correlation; far right, genes with high correlation and increased (red) or decreased (blue) expression and accessibility change. E TFs with differential activity based on chromatin accessibility change (ATAC-seq) around TF motifs and target gene expression change (RNA-seq) across the three FAD mutations relative to NDC using DiffTF with the CIS-BP motif database. F-G Schematic for intepareto ranking of genes characterized by ATAC-seq and RNA-seq to identify functional programs with the highest correlation of chromatin accessibility change and gene expression change; z-scores of log₂FC change of ATAC-seq peak accessibility change (promoter- or enhancer-located) and log₂FC of RNA-seq gene expression for each gene across all FAD mutations relative to NDC, followed by pareto optimization ranking for each gene and subsequent CERNO ranked geneset enrichment test. H-I intepareto-CERNO ranked enrichment using the (H) ENCODE-ChEA Consensus and ReMap TF-gene target databases (ENCODE, E; ChEA, C; ReMap, R) and (I) GOBP and Hallmark databases (Hallmark, H)