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.

Public Health Relevance

Successful completion of the proposed studies will reveal epigenetic induction of epithelial barrier dysfunction by EHMT2 as a novel mechanism of tobacco smoke-induced diseases. The results will validate the potential of EHMT2 as a therapeutic target to treat epithelial barrier dysfunction induced by environmental tobacco smoke exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES028752-01A1
Application #
9598390
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Tyson, Frederick L
Project Start
2018-08-01
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526