Fig. 4

Transcriptional effects of EP300/CBP KD in APPDup neurons. A, B EP300/CBP KD results in widespread transcriptional downregulation in APPDup neurons. Volcano plot of gene expression changes between EP300 KD vs CTRL siRNA (A) and CBP KD vs CTRL siRNA (B) in APPDup neurons. Significance and fold-change threshold of p-adj. < 0.005 and log2FC > 0.50 were used. C EP300 and CBP KD evoke generally similar transcriptional responses. Scatterplot depicting relationship of gene transcriptional changes between EP300 KD and CBP KD (rpearson = 0.62, p = 0.00) in APPDup neurons. D,E Venn diagram showing overlaps of gene expression changes between EP300 and CBP KD in APPDup neurons. Jaccard index = 646/2116 genes, p = 0.00000, hypergeometric test for overlaps between downregulated genes (D). Jaccard index = 99/989 genes; p = 0.00000, hypergeometric test for overlaps between upregulated genes (E). F, G KEGG-identified AD-associated genes are positively transcriptionally controlled by EP300 (F) and CBP (G) in APPDup neurons. Gene set enrichment analysis (GSEA) plot depicting placement of KEGG AD genes in transcriptome ranked from highest expressed in CTRL RNAi to highest expressed in EP300 (F) and CBP (E) KD in APPDup neurons. H Bubble plot depicting Gene Ontology (GO) terms identified by ClusterProfiler as significantly enriched in genes downregulated in both EP300 and CBP KD in APPDup neurons. Neuron-related terms are asterisked. I,J EGFR is a central interactor of genes significantly downregulated by EP300 and CBP KD in APPDup neurons. BioGRID-identified genetic interactions depicted by EasyNetworks (esyN) of genes significantly downregulated by EP300 (I) and CBP (J) KD. K EGFR transcription is higher in NDC neurons at baseline (+ CTRL RNAi) and is decreased by EP300/CBP KD in both APPDup and NDC neurons (p < 0.05 for all comparisons, unpaired two-tailed T-test). Normalized read-counts were obtained by RNA-Seq