UCLA

Macrophages exposed to immune stimuli reprogram their epigenomes to alter subsequent functions. Here, we have dissected the roles of interferon regulatory factors (IRFs) in innate immune de novo enhancer formation. We found that upon transient endotoxin exposure, such enhancers may remain poised for days. Endotoxin-activated IRF3 induces only a small number of de novo enhancers directly, but it is indirectly required for the formation of a large number of enhancers via type I interferon-induced ISGF3. However, ISGF3 is unable to trigger enhancer formation by itself – it must cooperate with NFκB-induced IRF1. In type II IFN, IRF1 induces enhancer formation by cooperating with GAF. We found that IRF1 is particularly required in locations that show less chromatin accessibility in naïve macrophages, and a fine timecourse revealed that IRF1 is required for the initial opening of chromatin before ISGF3 extends it and recruits enzymes to deposit H3K4me1 marks. Our results reveal an IRF1-mediated combinatorial logic gate to provide innate immune memory formation in cells exposed to pathogen or activated IFNγ-secreting T cells, but not bystander macrophages that benefit from the transient anti-viral message of type I interferon.