Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14. Issue 3 (1st March 2019)

• Record Type: Journal Article
• Authors: Miller, Daniel E; Forney, Carmy; Rochman, Mark; Cranert, Stacey; Habel, Jeffery; Rymer, Jeffrey; Lynch, Arthur; Schroeder, Connor; Lee, Josh; Sauder, Amber; Smith, Quinton; Chawla, Mehak; Trimarchi, Michael P; Lu, Xiaoming; Fjellman, Ellen; Brusilovsky, Michael; Barski, Artem; Waggoner, Stephen; Weirauch, Matthew T; Rothenberg, Marc E; Kottyan, Leah C
• Is Part Of: G3. Volume 9:Issue 3(2019)
• Page Start: 729
• Page End: 736
• Publication Date: 2019-03-01
• Subjects: CAPN14 -- Eosinophilic Esophagitis -- IL-13 -- IL-4 -- STAT6 -- Genetics of Immunity; Genetics -- Research -- Periodicals; Genomics -- Periodicals; Genetics; Genomics; Genes; Genetics -- Research; Genomics; Electronic journals; Periodical; Periodicals; Fulltext; Internet Resources; Periodicals; 572.8
• DOI: 10.1534/g3.118.200901
• Languages: English
• ISSNs: 2160-1836

Abstract

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.