Rescue of CREBBP and EP300 loading by saturating TF and local histone acetylation. (A) Western blot and schematic showing tetracycline-inducible IRF4 expression. (B) Density plots of H3K27Ac (left), EP300 (middle), and CREBBP (right) in RL (above) and HT (below) CREBBP Y1503C cells, relative to isogenic WT controls, showing regions that are predicted to be bound by IRF4. (C) Schematic showing the placement of dual-guide RNAs over the CD74 enhancer with reduced H3K27Ac in CREBBP KAT-PM cells compared with isogenic WT controls. (D) Representative flow cytometry plot showing fluorescent markers of each guide-RNA construct, enabling comparison of dual-positive and dual-negative populations. (E) Flow cytometry of CD74 expression in cells with no guide RNA (blue) or 2 guide RNAs (dual guides, red) for the dCas9-p300 system. (F) Fold change in the abundance of H3K27Ac, EP300, and CREBBP on the CD74 enhancer in no guide (blue) and dual-guide (red) populations, normalized to the no guide condition in WT cells.