ZC3H13 promotes ITGA6 m 6 A modification for chronic obstructive pulmonary disease progression

• Published in: Cellular signalling Vol. 120; p. 111190
• Main Authors: Xie, Bin, Dai, Ziyu, Jiang, Chen, Gao, Xufan, Yang, Shasha, Peng, Meijuan, Chen, Qiong, Chen, Xi
• Format: Journal Article
• Language: English
• Published: England 01.08.2024
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Apoptosis; Disease Models, Animal; Disease Progression; Humans; Integrin alpha6 - genetics; Integrin alpha6 - metabolism; Male; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Epithelial-mesenchymal transition; mA; Chronic obstructive pulmonary disease; ITGA6; ZC3H13

Chronic obstructive pulmonary disease (COPD) is potentially fatal, and as society ages, its effects on human health are predicted to deteriorate. The potential function of m6A modifications within COPD has become a hot topic recently. This study was conducted to clarify the function and related mechanisms of the m6A methylation transferase ZC3H13 in COPD. The expression of m6A-associated protease and ITGA6 in COPD tissues was assessed using GEO data, qRT-PCR, and western blot. COPD models in cells and mice were established through cigarette smoke extract (CSE) and smoke exposure. Inflammatory marker levels were measured by ELISA, apoptosis by flow cytometry, and mRNA stability with Actinomycin D assay. m6A modification levels were checked by MeRIP-PCR. HE and Masson staining evaluated lung pathology, and alveolar lavage fluid analysis included total cell count and Giemsa staining. ZC3H13 and METTL3 were differentially expressed m6A regulators in COPD, with ZC3H13 being more significantly upregulated. Further analysis revealed the ZC3H13 expression-related differentially expressed genes (DEGs) functions were enriched in the immunoinflammatory pathway, indicating ZC3H13's involvement in COPD pathogenesis through inflammation, and immune responses. Knockdown studies in cellular and mouse models demonstrated ZC3H13's role in exacerbating COPD symptoms, including inflammation, apoptosis, and EMT, and its suppression led to significant improvements. The identification of ITGA6 as a target gene further elucidated the mechanism, showing that ZC3H13 enhances ITGA6 expression and mRNA stability through m6A modification, influencing bronchial epithelial cell inflammation and fibrosis. In conclusion, targeting ZC3H13/ITGA6 could be an underlying therapeutic approach for treating COPD.