Macrophage reprogramming regulated by temporal and combinatorial signaling codes 2382

Description Immune sentinel cells must initiate the appropriate immune response upon sensing the presence of diverse pathogens or immune stimuli. To generate stimulus-specific responses, immune sentinel cells have evolved combinatorial and temporal signaling codes using a small number of stimulus-responsive transcription factors. Our recent studies have characterized how the transcription factors NFκB and IRF family members cause large scale changes in the epigenetic enhancer landscape. We identified about 4000 genomic locations that acquire the long-lasting enhancer mark H3K4me1 in response to LPS exposure, but not when macrophages are exposed to immune cytokines IFNß or TNF. I will describe how this specificity is mediated by temporal and combinatorial transcription factor control. Half of the epigenomic locations are induced by NFκB, but only when NFκB activity is non-oscillatory. This occurs when it is induced via the MyD88 pathway but not in response to TNF. Using mathematical modeling we identified the mechanism by which nucleosome displacement can be regulated via a temporal code (Science, 372, pp.1349, Cell Reports, 40, 111076). The other half are induced by IRF transcription factors. We found that these locations are induced by LPS but not IFNß, because IFNß-activated ISGF3 must collaborate with NFκB-activated IRF1 which displaces nucleosomes. Hence, these locations are regulated by combinatorial code of IRF family members (Science Signaling, in press). Funding Sources Supported by NIH/NIA R01AI173214 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)