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Genetic, inflammatory, and epithelial cell differentiation factors control expression of human calpain-14

By Daniel E. Miller, Carmy Forney, Mark Rochman, Stacey Cranert, Jeffery Habel, Jeffrey Rymer, Arthur Lynch, Connor Schroeder, Josh Lee, Amber Sauder, Quinton Smith, Mehak Chawla, Michael P. Trimarchi, Xiaoming Lu, Ellen Fjellman, Michael Brusilovsky, Artem Barski, Stephen N. Waggoner, Matthew T Weirauch, Marc E Rothenberg, Leah C. Kottyan

Posted 03 Jul 2018
bioRxiv DOI: 10.1101/359638 (published DOI: 10.1534/g3.118.200901)

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 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 establishes a candidate molecular mechanism for EoE disease etiology in which the risk variant at 2p23 dampens mediated CAPN14 expression in differentiated esophageal epithelial cells following IL-13/STAT6 induction of CAPN14 promoter activity.

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