not-yet-known not-yet-known not-yet-known unknown Human mast cell activation is regulated by super-enhancer activity and the associated cell-type specific transcriptional networks. Next, we set out to assess whether specific perturbation of super-enhancer activity can indeed affect human mast cell activation. To this end we treated primary human mast cells with JQ-1, a bromodomain containing 4 (BRD4) inhibitor 38, and induced degranulation by IgE/antigen stimulation. BRD4 is highly enriched at super-enhancer regions and actively regulates the expression of associated genes 39. JQ-1 potently inhibited primary human mast cell degranulation, in a concentration-dependent manner (Fig. 6A). JQ-1 did not induce cell death at the tested concentrations (data not shown). To assess whether the effects of JQ-1 were (non-)additive to the effects of butyrate on human mast cell activation, suboptimal concentrations of JQ-1 (50ng/mL) and butyrate (1mM), as well as a combination of the two inhibitors, were incubated with the cells for 24 h followed by IgE crosslinking. Inhibition of mast cell degranulation by butyrate was not further increased by (low-dose) JQ-1 addition, suggesting that both inhibitors target the same modulators of human mast cell activation (Fig. 6B). Indeed, JQ-1 repressed expression of various super-enhancer associated genes that were also repressed by butyrate (Fig. 6C, Supplementary Fig. 6A). LAIR, LCP2, LAT and LAT2 are essential modulators of human mast cell activation 40–43, which may explain why mast cells display an inhibited degranulation profile after both butyrate and JQ-1 exposure.