摘要：SummaryMast cells serve as a first-line defense of innate immunity. Interleukin-6 (IL-6) induced by bacterial lipopolysaccharide (LPS) in mast cells plays a crucial role in antibacterial protection. The zinc finger transcription factor GATA2 cooperatively functions with the ETS family transcription factor PU.1 in multiple mast cell activities. However, the regulatory landscape directed by GATA2 and PU.1 under inflammation remains elusive. We herein showed that a large proportion of GATA2-binding peaks were closely located with PU.1-binding peaks in distalcis-regulatory regions of inflammatory cytokine genes in mast cells. Notably, GATA2 and PU.1 played crucial roles in promoting LPS-mediated inflammatory cytokine production. Genetic ablation of GATA2-PU.1-clustered binding sites at theIl6-39 kb region revealed its central role in LPS-inducedIl6expression in mast cells. We demonstrate a novel collaborative activity of GATA2 and PU.1 in cytokine induction upon inflammatory stimuli via the GATA2-PU.1 overlapping sites in the distalcis-regulatory regions.Graphical abstractDisplay OmittedHighlights•GATA2- and PU.1-binding peaks are closely located in distal enhancers of cytokine genes•GATA2 and PU.1 play crucial roles in promoting LPS-mediated cytokine induction•TheIl6-39 kb enhancer containing GATA2 and PU.1 motifs are crucial forIl6induction•GATA2 inhibitor exerts anti-inflammatory effects via reducing cytokine inductionMolecular biology; Molecular mechanism of gene regulation; Immunology.
