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

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

Published In Sci Rep, (2019 05 14)

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.

PubMed ID: 31089182 Exiting the NIEHS site

MeSH Terms: Allergens/administration & dosage; Allergens/immunology; Animals; Antigens, Dermatophagoides/administration & dosage; Antigens, Dermatophagoides/immunology; Asthma/immunology; Asthma/physiopathology*; Basic Helix-Loop-Helix Transcription Factors/metabolism*; Bronchi/immunology; Bronchi/pathology; Bronchi/physiopathology; Bronchial Hyperreactivity/diagnosis; Bronchial Hyperreactivity/immunology*; Bronchial Hyperreactivity/pathology; Bronchoalveolar Lavage Fluid/cytology; Bronchoalveolar Lavage Fluid/immunology; Cell Line; DNA Methylation/immunology; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism*; Disease Models, Animal; Down-Regulation/immunology; Epithelial Cells/immunology; Epithelial Cells/pathology; Gene Knockdown Techniques; Humans; Interferons/metabolism*; Mice; Mice, Knockout; Mixed Function Oxygenases/genetics; Mixed Function Oxygenases/metabolism*; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism*; RNA, Small Interfering/metabolism; RNA-Seq; Receptors, Aryl Hydrocarbon/metabolism*; Respiratory Mucosa/cytology; Respiratory Mucosa/immunology; Respiratory Mucosa/pathology; Signal Transduction/immunology; Up-Regulation/immunology

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Last Reviewed: October 02, 2024