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

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Eosinophilic esophagitis (EoE) is a chronic allergic condition causing esophageal inflammation.
• EoE susceptibility is linked to genetic variants in the CAPN14 gene promoter.
• CAPN14 expression is upregulated by disease activity and IL-13, with specific expression in the esophagus.

Purpose of the Study:

• To investigate the molecular mechanisms regulating CAPN14 gene expression.
• To identify transcription factors and signaling pathways involved in CAPN14 modulation.
• To understand the role of genetic variants in CAPN14 regulation in EoE.

Main Methods:

• Luciferase reporter assays to assess CAPN14 promoter activity.
• Identification of STAT6 binding sites in the CAPN14 promoter and intron.
• Chromatin immunoprecipitation to confirm STAT6 binding.
• Analysis of CAPN14 expression in differentiated esophageal epithelial cells stimulated with IL-13/IL-4.

Main Results:

• Three STAT6 binding sites were identified in the CAPN14 promoter and first intron.
• IL-13/IL-4 stimulation significantly increased CAPN14 promoter activity, dependent on STAT6 binding sites.
• A disease-associated risk variant reduced IL-13-induced promoter activity.
• Highest CAPN14 expression was observed in differentiated esophageal cells stimulated with IL-13/IL-4.

Conclusions:

• STAT6 directly binds to the CAPN14 promoter and mediates IL-13/IL-4 induced expression.
• The identified genetic risk variant may dampen CAPN14 expression in differentiated esophageal cells.
• This provides a molecular mechanism linking genetic predisposition, IL-13 signaling, and EoE pathogenesis.