Fig. 4

Transcriptome-wide impact of epigenetic probes on core regulatory TF transcription. a Chemical informer set of epigenetic probes reveals selective effect on transcription of core regulatory TF genes associated with super enhancers, as compared to all TFs, housekeeping TFs, and TFs not SE-associated. Gene set enrichment analysis was performed on RNA-seq measured gene-level transcripts from 6 h treatments with indicated compounds. Size and color of circles are proportional to GSEA enrichment scores. Mechanistic class is indicated to the left of compound names, whose particular protein isoform targets are indicated on the right. Called out example enrichment plots for CR TFs show strong negative enrichment for pan-isoform HDAC inhibitor LAQ824 and inhibitor of p300 bromodomains SGCCBP30 (with false discovery rates < 0.0001). b Suppression of RNA expression of core regulatory TFs upon inhibition of readers, writers, and erasers of the acetylation axis (HDAC, p300 or BRD4), but not by lysine methylation axis (EZH2, G9a, LSD1, JMJD3, or L3MBTL3). Exon level expression changes were quantified from RNA-seq after 6 h of drug treatment, compared to DMSO controls. c Changes in protein-coding genes upon HDAC inhibition with three distinct pharmacophores: hydroxamic acid (LAQ824), benzamide (Merck60), and epoxide (NS1302) zinc-binding groups. Overlap in gene sets for increased and decreased genes are shown above and below, respectively. d Rank order of change in TF gene expression upon HDAC inhibition, with core regulatory TFs highlighted in green. Values are the average delta FPKM across LAQ824, Merck60, and NS1302. Count histogram of CR TF rank is graphed on the right. e Core regulatory TFs are significantly more sensitive to HDAC inhibitors than other TFs, but all TFs (including CR TFs) are also more sensitive than all non-TF genes. Box plots (center line = median, box bounds = quartiles, whiskers = 1.5*inter-quartile range) show log₂-fold change in HDACi versus control DMSO. ****P-value < 0.0001 as calculated by a two-tailed t-test with Welch’s correction