Role of TET1 in airway epithelium and childhood asthma

TET1 在气道上皮和儿童哮喘中的作用

• 批准号: 10618366
• 负责人: Hong Ji
• 金额: $ 58.99万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618366
• 关键词: Address; Affect; Allergens; Allergic Disease; Asthma; Binding; Binding Sites; Child; Childhood; Childhood Asthma; Chromatin; Chronic; Chronic Disease; DNA Methylation; Data; Dependence; Development; Dioxygenases; Disease; Down-Regulation; Emergency Care; Environmental Exposure; Epigenetic Process; Epithelial Cells; Epithelium; Etiology; Exposure to; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Histones; Hospitalization; Human; Innate Immune Response; Interferon Type I; Interferons; Knockout Mice; Knowledge; Lung; Measurement; Measures; Mediating; Methylation; Modeling; Modification; Molecular; Mus; Nasal Epithelium; Pathogenesis; Pathway interactions; Phenotype; Proteins; Public Health; Pulmonary Inflammation; Pyroglyphidae; Regulation; Repression; Research; Risk; Role; STAT1 gene; STAT2 gene; Severities; Signal Pathway; Signal Transduction; Stimulus; Symptoms; Testing; Transcriptional Regulation; Translating; United States; Up-Regulation; Viral Respiratory Tract Infection; Virus; adaptive immune response; airway epithelium; airway hyperresponsiveness; asthma exacerbation; asthma model; asthmatic; asthmatic airway; bronchial epithelium; cell type; epigenetic regulation; epigenome; gene function; gene network; gene repression; histone modification; in vivo; individualized medicine; insight; mRNA Expression; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; promoter; protein complex; recruit; respiratory virus; single-cell RNA sequencing; transcription factor

Project Summary Asthma is the most common chronic disease among children and the leading cause of emergency care and hospitalization in children. Even though multiple asthma therapies exist, the high rate of incomplete efficacy in asthma treatment (40%-70%) highlights the need for alternative individualized therapies based on a better un- derstanding of disease mechanisms. To date, the molecular mechanisms underlying the etiology and patho- genesis of childhood asthma are not fully understood. This proposal directly fills in this gap in knowledge and tests a novel hypothesis addressing disease mechanism. Methylcytosine dioxygenase TET1 modifies 5’- methyl-cytosine and regulate gene function. In addition to its catalytic activity, TET1 protein recruits histone modifying protein complexes through interaction with transcription factors (TFs) to regulate histone marks and chromatin accessibility, leading to both activation and repression of gene expression. We were the first to show that in airway epithelial cells, higher TET1 promoter methylation is associated with lower TET1 expression and more frequent asthma symptoms in children. Further, we found that overexpression of TET1 in HBECs (human bronchial epithelial cells) leads to transcriptional downregulation of interferon (IFN) signaling pathway. Consist- ently, loss of TET1 in HBECs significantly increases the expression of IRF7 and its downstream target type I IFN following HDM challenges. Finally, loss of Tet1 causes increased lung expression of IFN signaling path- way and leads to enhanced airway hyperresponsiveness and lung inflammation in mouse models of asthma. Collectively, these data support an overall protective role of TET1 in asthma severity through inhibition of type I IFN signaling. Our data strongly implicate a protein/protein interaction network including IRF7/STAT1/STAT2 in mediating the effects of TET1 on type I IFN induction. Preliminary analysis supports the regulation of IRF7 ex- pression by TET1 through DNA methylation and histone modification. It is well established that airway epitheli- al type I IFN signaling pathway regulates innate and adaptive immune responses to external stimuli and con- tributes to asthma development and exacerbation. Collectively, we hypothesize that Tet1 regulates asthma phenotypes by inhibiting type I interferon signaling through DNA methylation and histone modifications in air- way epithelial cells. Our long-term goal is to understand the epigenetic regulation of childhood asthma. The objective of this R01 application is to identify the mechanism(s) by which TET1 contributes to asthma. This ap- plication will have significant public health impact. Through the proposed aims, we will 1) demonstrate that the transcriptional regulation of type I IFN signaling pathway by TET1 in airway epithelium modulates asthma phe- notypes; 2) define the mechanism(s) by which TET1 regulates type I IFN signaling pathway in normal and asthmatic epithelium; 3) show that Tet1 regulates respiratory virus-induced asthma exacerbation; and 4) pro- vide novel therapeutic targets for asthma and other diseases in which type I IFN signaling pathway is an es- sential player.

项目总结

项目成果

Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk.

• DOI: 10.2217/epi-2020-0424
• 发表时间: 2021-04
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: V. Chidambaran;Xue Zhang;Valentina Pilipenko;Xiaoting Chen;Benjamin Wronowski;Kristie Geisler;Lisa J. Martin;A. Barski;M. Weirauch;H. Ji

Decoding the exposome: data science methodologies and implications in exposome-wide association studies (ExWASs).

解码暴露组：数据科学方法及其对全暴露组关联研究（ExWAS）的影响。

• DOI: 10.1093/exposome/osae001
• 发表时间: 2024
• 期刊: Exposome
• 作者: Chung,MingKei;House,JohnS;Akhtari,FaridaS;Makris,KonstantinosC;Langston,MichaelA;Islam,KhandakerTalat;Holmes,Philip;Chadeau-Hyam,Marc;Smirnov,AlexI;Du,Xiuxia;Thessen,AnneE;Cui,Yuxia;Zhang,Kai;Manrai,ArjunK;Motsinger-Re
• 通讯作者: Motsinger-Re

The "epiTet" of Air Pollution: Epigenetic Regulation of Airway Inflammation by Tet1.

• DOI: 10.1159/000530272
• 发表时间: 2023
• 期刊: International archives of allergy and immunology
• 影响因子: 2.8