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Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14.

Miller DE, Forney C, Rochman M, Cranert S, Habel J, Rymer J, Lynch A, Schroeder C, Lee J, Sauder A, Smith Q, Chawla M, Trimarchi MP, Lu X, Fjellman E, Brusilovsky M, Barski A, Waggoner S, Weirauch MT, Rothenberg ME, Kottyan LC

Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease resulting in eosinophilic esophageal inflammation. We recently found that EoE susceptibility is associated with genetic variants in the promoter of , a gene with reported esophagus-specific expression. is dynamically up-regulated as a function of EoE disease activity and after exposure of epithelial cells to interleukin-13 (IL-13). Herein, we aimed to explore molecular modulation of expression. We identified three putative binding sites for the IL-13-activated transcription factor STAT6 in the promoter and first intron of Luciferase reporter assays revealed that the two most distal STAT6 elements were required for the ∼10-fold increase in promoter activity subsequent to stimulation with IL-13 or IL-4, and also for the genotype-dependent reduction in IL-13-induced promoter activity. One of the STAT6 elements in the promoter was necessary for IL-13-mediated induction of promoter activity while the other STAT6 promoter element was necessary for full induction. Chromatin immunoprecipitation in IL-13 stimulated esophageal epithelial cells was used to further support STAT6 binding to the promoter of at these STAT6 binding sites. The highest and calpain-14 expression occurred with IL-13 or IL-4 stimulation of esophageal epithelial cells under culture conditions that allow the cells to differentiate into a stratified epithelium. This work corroborates a candidate molecular mechanism for EoE disease etiology in which the risk variant at 2p23 dampens expression in differentiated esophageal epithelial cells following IL-13/STAT6 induction of promoter activity.

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March, 2019


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