Interleukin-12 drives a rapid STAT4/DDX5-dependent change in the RNA polymerase II landscape for IFN-γ production by NK cells [CUT&RUN]

Natural killer (NK) cells are innate lymphocytes that respond to inflammatory cytokines produced during infection by mounting a rapid response. However, the mechanisms that allow NK cells to launch such a swift response upon inflammation remains incompletely understood. Here, we investigate whether RNA Polymerase II (Pol II) may regulate this rapid responsiveness of NK cells. Exposure of NK cells to the proinflammatory cytokine interleukin-12 (IL-12) results in a highly dynamic Pol II genomic landscape mediated by the transcription factor STAT4, especially at the interferon-gamma (Ifng) locus. We identify a STAT4 interacting partner, the RNA helicase DDX5, that was required for optimal IFN-γ production by modulating Pol II occupancy following IL-12 stimulation. Thus, our findings highlight STAT4/DDX5-mediated regulation of Pol II binding as a critical mechanism driving the rapid responsiveness of NK cells to proinflammatory cytokines.