lBromodomain inhibitor JQ1 reversibly blocks IFN-gamma production

As a class, 'BET' inhibitors disrupt binding of bromodomain and extra-terminal motif (BET) proteins, BRD2, BRD3, BRD4 and BRDT, to acetylated histones preventing recruitment of RNA polymerase 2 to enhancers and promoters, especially super-enhancers, to inhibit gene transcription. As such, BET inhibitors may be useful therapeutics for treatment of cancer and inflammatory disease. For example, the small molecule BET inhibitor, JQ1, selectively represses MYC, an important oncogene regulated by a super-enhancer. IFN-gamma, a critical cytokine for both innate and adaptive immune responses, is also regulated by a super-enhancer. Here, we show that JQ1 represses IFN-gamma expression in TH1 polarized PBMC cultures, CD4+ memory T cells, and NK cells. JQ1 treatment does not reduce activating chromatin marks at the IFNG locus, but displaces RNA polymerase II from the locus. Further, IFN-gamma expression recovers in polarized TH1 cultures following removal of JQ1. Our results show that JQ1 abrogates IFN-gamma expression, but repression is reversible. Thus, BET inhibitors may disrupt the normal functions of the innate and adaptive immune response.