ZC3H13 promotes ITGA6 m6A modification for chronic obstructive pulmonary disease progression

Bin Xie; Ziyu Dai; Chen Jiang; Xufan Gao; Shasha Yang; Meijuan Peng; Qiong Chen; Xi Chen

doi:10.1016/j.cellsig.2024.111190

ZC3H13 promotes ITGA6 m⁶A modification for chronic obstructive pulmonary disease progression

Cell Signal. 2024 Apr 24:111190. doi: 10.1016/j.cellsig.2024.111190. Online ahead of print.

Authors

Bin Xie¹, Ziyu Dai¹, Chen Jiang¹, Xufan Gao¹, Shasha Yang¹, Meijuan Peng¹, Qiong Chen¹, Xi Chen²

Affiliations

¹ Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Changsha, Hunan, 410008, China. Electronic address: chenxi7116@163.com.

PMID: 38670474
DOI: 10.1016/j.cellsig.2024.111190

Abstract

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.

Keywords: Chronic obstructive pulmonary disease; Epithelial-mesenchymal transition; ITGA6; ZC3H13; m(6)A.