TY - JOUR
T1 - Epigenetic Reprogramming Drives Epithelial Disruption in Chronic Obstructive Pulmonary Disease
AU - Yeung-Luk, Bonnie H.
AU - Wally, Ara
AU - Swaby, Carter
AU - Jauregui, Sofia
AU - Lee, Esther
AU - Zhang, Rachel
AU - Chen, Daniel
AU - Luk, Sean H.
AU - Upadya, Nisha
AU - Tieng, Ethan
AU - Wilmsen, Kai
AU - Sherman, Ethan
AU - Sudhakar, Dheeksha
AU - Luk, Matthew
AU - Shrivastav, Abhishek Kumar
AU - Cao, Shuo
AU - Ghosh, Baishakhi
AU - Christenson, Stephanie A.
AU - Huang, Yvonne J.
AU - Ortega, Victor E.
AU - Biswal, Shyam
AU - Tang, Wan Yee
AU - Sidhaye, Venkataramana K.
N1 - Publisher Copyright:
© 2024 by the American Thoracic Society.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-29-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.
AB - Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-29-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.
KW - CDH1
KW - COPD
KW - DNA methylation
KW - E-cadherin
KW - epigenetic
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U2 - 10.1165/rcmb.2023-0147OC
DO - 10.1165/rcmb.2023-0147OC
M3 - Article
C2 - 37976469
AN - SCOPUS:85186744446
SN - 1044-1549
VL - 70
SP - 165
EP - 177
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 3
ER -