EZH2 is a molecular determinant of epithelial cell hyperresponsiveness and severe airway disease 4524

Abstract Description Asthma is a chronic hyperinflammatory disorder characterized by airway hyperresponsiveness (AHR). Current asthma treatments primarily focus on symptom management and prevention of exacerbations, but they often fail during severe episodes. In a comprehensive screening of bronchial airway epithelial cells (BAEC) from patients with severe asthma, we observed the downregulation of multiple components of the Polycomb Repressive Complex 2 (PRC2), including EZH2. EZH2 is a histone modification protein known to catalyze the trimethylation of H3K27me3 to maintain transcriptional repression, acting as a molecular brake on gene transcription. Epigenetic factors, including histone modifications, are increasingly recognized as key determinants of immune responses; however, the immunomodulatory function of EZH2 in BAEC remains unknown. We hypothesized that the observed reduction in EZH2 renders BAEC hypersensitive to non-specific stimuli. Mechanistically, we discovered that viral stimulation or canonical interferon signaling directly inhibits EZH2 via STAT-mediated transrepression, thereby priming the inflammatory response to secondary stimuli. Using genetic gain- and loss-of-function approaches in vivo, we confirmed the critical role of EZH2 in regulating cytokine and cellular responses in the airway. Our findings provide a deeper understanding of the molecular mechanisms driving airway inflammation and offer insights into mitigating AHR in patients with severe airway disease. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)