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Role of EHMT2 in tobacco smoke-induced epithelial barrier dysfunction

EHMT2 在烟草烟雾诱导的上皮屏障功能障碍中的作用

基本信息

批准号：
9751303
负责人：
Jian Fu
金额：
$ 19.13万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751303
关键词：
Adherens Junction Cardiovascular Diseases Cells Cellular Structures Chronic Data Defect Disease Down-Regulation E-Cadherin Environmental Tobacco Smoke Epigenetic Process Epithelial Epithelial Cells Euchromatin Exposure to Functional disorder Gene Expression Gene Expression Regulation Histone H3 Histone-Lysine N-Methyltransferase Human Infection Inflammation Injury Intercellular Junctions Lung Lung diseases Lysine Methylation Modification Molecular Pathogenesis Play Reporting Role Structure of parenchyma of lung Testing Therapeutic Tobacco smoke Toxic Environmental Substances Up-Regulation airway epithelium cadherin 10 cigarette smoke cigarette smoke-induced environmental tobacco smoke exposure exposed human population exposure to cigarette smoke histone methyltransferase histone modification in vivo interstitial knock-down mouse model new therapeutic target novel prevent promoter recruit therapeutic target

项目摘要

Project Summary Epithelial barrier dysfunction contributes to the pathogenesis of infection, inflammation and injury. E-Cadherin, a component of epithelial adherens junctions, plays an essential role in maintaining epithelial barrier function. Cigarette smoke exposure has been reported to downregulate E-Cadherin expression in epithelial cells. However, molecular mechanisms of cigarette smoke-induced suppression of E-Cadherin expression and epithelial barrier dysfunction remain largely unknown. In this project, we will investigate the role of a histone methyltransferase, euchromatic histone-lysine N-methyltransferase 2 (EHMT2 or G9a), in cigarette smoke-induced E-cadherin downregulation and epithelial barrier dysfunction. EHMT2 specifically methylates Histone H3 at lysine 9 (H3K9). Methylation of H3K9 by EHMT2 regulates gene expression by silencing euchromatin. Our preliminary data demonstrate that EHMT2 expression is robustly up-regulated in cigarette smoke-exposed normal human bronchial epithelial cells (NHBEs). The up-regulation of EHMT2 is associated with high levels of H3K9 methylation and E-Cadherin downregulation. EHMT2 knockdown or selective inhibition was able to restore E-Cadherin expression in cigarette smoke-exposed NHBEs. Furthermore, in a mouse model of cigarette smoke exposure, lung EHMT2 expression and H3K9 methylation were increased, which was associated with E-cadherin downregulation and epithelial barrier disruption in lung tissues. In the proposed studies, we will test we will test the hypothesis that EHMT2 up-regulation by chronic tobacco smoke exposure leads to epigenetic suppression of E-Cadherin expression and epithelial barrier dysfunction. Our specific aims are: (1) To determine the role of EHMT2 in epigenetic suppression of E-Cadherin expression and epithelial barrier dysfunction in tobacco smoke-exposed human bronchial epithelial cells. (2) To explore therapeutic mechanisms of EHMT2 inhibition against tobacco smoke-induced epithelial barrier dysfunction in vivo. Our studies could reveal new therapeutic targets to treat environmental tobacco smoke-induced epithelial cell dysfunction.

项目总结