Dataset Information

Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling.

ABSTRACT: Allergic asthma is a chronic inflammatory airway disease whose clinical course is punctuated by acute exacerbations from aeroallergen exposure or respiratory virus infections. Aeroallergens and respiratory viruses stimulate toll-like receptor (TLR) signaling, producing oxidative injury and inflammation. Repetitive exacerbations produce complex mucosal adaptations, cell-state changes, and structural remodeling. These structural changes produce substantial morbidity, decrease lung capacity, and impair quality of life. We will review recent systems-level studies that provide fundamental new insights into how repetitive activation of innate signaling pathways produce epigenetic 'training' to induce adaptive epithelial responses. Oxidative stress produced downstream of TLR signaling induces transient oxidation of guanine bases in the regulatory regions of inflammatory genes. The epigenetic mark 8-oxoG is bound by a pleiotropic DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), which induces conformational changes in adjacent DNA to recruit the NFκB·bromodomain-containing protein 4 (BRD4) complex. The NFκB·BRD4 complex not only plays a central role in inflammation, but also triggers mesenchymal transition and extracellular matrix remodeling. Small molecule inhibitors of OGG1-8-oxoG binding and BRD4-acetylated histone interaction have been developed. We present studies demonstrating efficacy of these in reducing airway inflammation in preclinical models. Targeting inducible epigenetic reprogramming pathway shows promise for therapeutics in reversing airway remodeling in a variety of chronic airway diseases.

SUBMITTER: Brasier AR

PROVIDER: S-EPMC6821469 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling.

Brasier Allan R AR Boldogh Istvan I

Drugs in context 20191023

Allergic asthma is a chronic inflammatory airway disease whose clinical course is punctuated by acute exacerbations from aeroallergen exposure or respiratory virus infections. Aeroallergens and respiratory viruses stimulate toll-like receptor (TLR) signaling, producing oxidative injury and inflammation. Repetitive exacerbations produce complex mucosal adaptations, cell-state changes, and structural remodeling. These structural changes produce substantial morbidity, decrease lung capacity, and im ...[more]

PMID: 31692901

Similar Datasets

Project description:BackgroundViruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms.ObjectivesTo identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model.MethodsAirway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP.ResultsWe identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p < .01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways.ConclusionRV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

Dataset Information

Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling.

Publications

Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets