Asthma is the most frequent chronic disease among children. Although the airway epithelium is a major driver of the allergic responses in the etiology of asthma, no current asthma treatments specifically target the airway epithelium. Standard asthma treatments including bronchodilators and corticosteroids are not completely effec- tive in all asthmatics, especially in those with severe diseases, indicating a great need fo alternative personal- ized asthma therapy. As a DNA demethylase that converts 5mC to 5hmC, the role of TET1 in stem cell maintenance, neural activity and cancer have recently been revealed. However, the role of TET1 in asthma is unknown. From our pilot Exposure Sibling Study, we found that the promoter methylation of TET1 is decreased in asthmatic children compared to non-asthmatics in airway epithelial cells, and this lower methylation level correlates with higher expression levels of TET1. This increase in TET1 expression in asthmatics is also asso- ciated with a significant increase in 5hmC level. Based on these intriguing and novel observations, we hypoth- esize that TET1 contributes to asthma through increasing hydroxyl-methylation of its target genes in the airway epithelium. Our long-term goal is to understand the role of TET1 in asthma pathogenesis and explore its thera- peutic potentials. The objective of this R21 application is to establish the association of TET1 with asthma and to identify its target asthma genes in the airway epithelium, which is a logical step towards a subsequent R01 application aiming to further understand the detailed contributions of TET1 in asthma. Our study will be the first to establish the role of TET1 in regulating asthma genes in airway epithelial cels. Using samples from two in- dependent cohorts and human primary airway epithelial cells, we propose to test our hypothesis using the fol- lowing specific aims: 1) to determine whether TET1 methylation and expression are associated with asthma, 2) to determine the target genomic locations of TET1 in airway epithelial cells. We expect our novel study will demonstrate that TET1 regulates the expression of its target asthma genes through hydroxylation of their pro- moters. The research proposed in this R21 is significant because it will establish the association of TET1 and its product 5hmC with asthma and asthma phenotypes in children and identify their target genes in the airway epithelium. This will open the door for future research aiming to further understand the roles of TET1 and 5hmC in asthma development using animal models and other available tools, which may result in the devel- opment of novel asthma therapy and have broader impact in other diseases related to TET1.
Asthma is one of the most common chronic disorders in childhood, yet the heterogeneous nature of asthma and great variability among patients' individual therapeutic responses highlights the need for alternative individualized therapies based on the mechanisms of the disease. TET1 is a DNA demethylase implicated in diseases such as cancer and depression; however, the role of TET1 in asthma is unknown. Our proposed research aims to establish a novel role of TET1 in asthma, which may ultimately lead to the development of novel asthma therapies.
