Targeting a central feature of asthma using a cell type-selective IL-13-responsive enhancer

IL-13 is a central mediator of asthma1-3. Here, we used genome-wide approaches to characterize genes and regulatory elements modulated by IL-13 and other asthma-associated cytokines in airway epithelial cells and showed how they can be used for therapeutic purposes. Using bulk and single cell RNA-seq, we found distinctive responses to IL-13, IL-17, and interferons in human bronchial epithelial basal, ciliated, and secretory cells. H3K27ac ChIP-seq revealed that IL-13 had widespread effects on regulatory elements. Detailed characterization of an enhancer of SPDEF, a transcription factor required for pathologic mucin production, revealed that STAT6 and KLF5 binding sites cooperate to drive IL-13-dependent transcription selectively in secretory cells. Using this enhancer to drive CRISPRi and knockdown either SPDEF or the mucin MUC5AC showed the potential use of this approach for asthma therapeutics. This work identifies numerous genes and regulatory elements involved in cell type-selective cytokine responses and showcases their use for therapeutic purposes.