Under normal conditions (NL) esophageal epithelium is characterized by strong intercellular contacts, and barrier integrity is preserved. In the homeostatic esophagus, SYNPO is expressed at the basal layer of the esophageal epithelium and interacts with actin filaments. SYNPO is transcribed at low levels, and its promoter is decorated by low levels of activating epigenetic marks. In EoE, IL-13 is secreted by tissue-resident lymphocytes, causing STAT-6–dependent transcriptional activation of SYNPO in esophageal epithelium accompanied by elevated levels of activating epigenetic marks in the promoter of SYNPO gene. Basal zone hyperplasia and expansion of SYNPO expression into the suprabasal layers of the esophagus are evident. Subsequently, epithelial barrier integrity is altered and eosinophils penetrate esophageal mucosa. Treatment of EoE patients with anti–IL-13 antibody or knocking down STAT6 in esophageal epithelial cells counteracts IL-13–dependent transcriptional and epigenetic changes of SYNPO. Note that cell nuclei are omitted for clarity.