{Reference Type}: Journal Article
{Title}: Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14.
{Author}: 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;
{Journal}: G3 (Bethesda)
{Volume}: 9
{Issue}: 3
{Year}: 03 2019 7
{Factor}: 3.542
{DOI}: 10.1534/g3.118.200901
{Abstract}: 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 CAPN14, a gene with reported esophagus-specific expression. CAPN14 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 CAPN14 expression. We identified three putative binding sites for the IL-13-activated transcription factor STAT6 in the promoter and first intron of CAPN14 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 CAPN14 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 CAPN14 at these STAT6 binding sites. The highest CAPN14 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 CAPN14 expression in differentiated esophageal epithelial cells following IL-13/STAT6 induction of CAPN14 promoter activity.