TET1 contributes to allergic airway inflammation and regulates interferon and aryl hydrocarbon receptor signaling pathways in bronchial epithelial cells

J D Burleson,Hong Ji,Dylan Siniard,Matthew T Weirauch,Xiaoting Chen,Brandy P Ruff,Veda K Yadagiri,Gurjit K Khurana Hershey,Eric B Brandt

doi:10.1038/s41598-019-43767-6

Abstract

Previous studies have suggested a role for Tet1 in the pathogenesis of childhood asthma. However, how Tet1 contributes to asthma remains unknown. Here we used mice deficient for Tet1 in a well-established model of allergic airway inflammation and demonstrated that loss of Tet1 increased disease severity including airway hyperresponsiveness and lung eosinophilia. Increased expression of Muc5ac, Il13, Il33, Il17a, Egfr, and Tff2 were observed in HDM-challenged Tet1-deficient mice compared to Tet1+/+ littermates. Further, transcriptomic analysis of lung RNA followed by pathway and protein network analysis showed that the IFN signaling pathway was significantly upregulated and the aryl hydrocarbon receptor (AhR) pathway was significantly downregulated in HDM-challenged Tet1−/− mice. This transcriptional regulation of the IFN and AhR pathways by Tet1 was also present in human bronchial epithelial cells at base line and following HDM challenges. Genes in these pathways were further associated with changes in DNA methylation, predicted binding of transcriptional factors with relevant functions in their promoters, and the presence of histone marks generated by histone enzymes that are known to interact with Tet1. Collectively, our data suggest that Tet1 inhibits HDM-induced allergic airway inflammation by direct regulation of the IFN and AhR pathways.

Highlights

Asthma is one of the most common chronic disorders in childhood[1], currently affecting an estimated 6.2 million children under 18 years, of which 3.1 million suffered from an asthma attack or episode in 20152
We found that loss of Tet[1] increased the severity of allergic airway disease, most notably airway hyperresponsiveness (AHR), in a mouse model exposed to the common allergen house dust mite (HDM)
Integrative transcriptomic analysis, pathway and network analyses revealed the upregulation of genes in the IFN signaling pathway and downregulation of genes in the Aryl hydrocarbon Receptor (AhR) signaling pathway in Tet1-deficient lungs challenged by HDM

Summary

Introduction

Asthma is one of the most common chronic disorders in childhood[1], currently affecting an estimated 6.2 million children under 18 years, of which 3.1 million suffered from an asthma attack or episode in 20152. Studies of lung tissues from a mouse model of experimental asthma identified DNA methylation changes related to smooth muscle functions in mice with allergic asthma[16,17]. The expression of TET1 is regulated by asthma-related exposures such as diesel exhaust particles and house dust mite (HDM) in human bronchial epithelial cells[8,9] and in whole lungs of mice[16]. We performed DNA methylation studies and functional genomic analyses to understand how Tet[1] regulates gene expression in the airways. Our data from both mouse models and human bronchial epithelial cells strongly support that Tet[1] suppresses allergic airway inflammation by transcriptional regulation of Interferon (IFN) and Aryl hydrocarbon Receptor (AhR) signaling pathways through changes in DNA methylation, and interactions with particular transcription factors and histone modifiers

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Results

Conclusion