Epigenetic and Transcriptional Programming of Esophageal Eosinophils by the Local Tissue Environment [ATAC-seq]

Tissue eosinophilia is a hallmark feature of allergic diseases. Eosinophils resident in different tissues have unique properties, and whether that heterogeneity is stochastic or regulated by cell-intrinsic or extrinsic factors has not been established. We profiled tissue eosinophils in the esophagus during allergic inflammation using single-cell sequencing, epigenomic mapping, and flow cytometry. Human and murine esophageal eosinophils exhibited a specialized transcriptional and epigenetic landscape, composed of metabolic, extracellular sensing, and immunomodulatory genes, and enriched for AP-1 transcription factor binding sites. Additionally, human esophageal eosinophils were enriched for genes present within allergic disease risk loci and genes that correlated with the degree of esophageal eosinophilia. Furthermore, the esophageal eosinophil molecular signature was regulated by interactions between eosinophils and esophageal epithelial cells. Taken together, we determined that esophageal eosinophils are programmed through interactions with epithelial cells by interplay of local tissue extrinsic factors that operate through a transcription factor complex containing AP-1. We performed ATAC-seq on FACS-sorted esophageal and bone marrow eosinophils (CCR3 high and CCR3 low bone marrow eosinophils) isolated from CC10-iIL13Tg mice. Experiments were performed in two to four replicates per group, each replicate was pooled from 6-10 mice.