Antigen and IL-33 synergistically promote chromatin accessibility at the regulatory regions of pro-inflammatory genes of human skin mast cells

Antigenic stimulation through cross-linking the IgE receptor and epithelial cell-derived cytokine IL-33 are potent stimuli of mast cell (MC) activation. However, target genes induced by the combined antigen and IL-33 stimulation have not been investigated in human skin mast cells in a genome-wide manner. Furthermore, epigenetic mechanisms by which IL-33 acts synergically with antigenic stimulation to induce gene transcription have not been investigated. We identified the target genes that responded to the combined antigen and IL-33 stimulation using RNA-seq. These genes can be divided into three groups. Genes in the first group are target genes where antigenic stimulation and IL-33 stimulation achieve high levels of synergy in promoting these gene transcription (high synergy target genes). Genes in the second group are target genes for low levels of synergy mediated by the combined antigen and IL-33 stimulation (low synergy target genes). And genes in the third group are not targeted for the antigen and IL-33 synergy (non-synergy target genes). We found that pro-inflammatory cytokine and chemokine genes were enriched among the high synergy target genes. We demonstrate that the combined antigen and IL-33 stimulation-induced or -increased chromatin accessible areas in the regulatory regions of the high synergy target genes but not of the low synergy target genes. Transcription factor binding motif analysis revealed more binding sites for NF-κB, AP-1, GABPA, and RAP1 in the induced or increased chromatin accessible regions of the high synergy target genes. Our study shines a light on an epigenetic mechanism by which how epithelial cell-derived cytokine IL-33 might cause exacerbation of skin MC-mediated allergic inflammation. ### Competing Interest Statement The authors have declared no competing interest.