Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling

Allan R. Brasier, Istvan Boldogh

Research output: Contribution to journalReview article

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.

Original languageEnglish (US)
Article number2019-8-3
JournalDrugs in Context
Volume8
DOIs
StatePublished - Jan 1 2019

Fingerprint

Airway Remodeling
Epigenomics
Toll-Like Receptors
Inflammation
DNA Glycosylases
DNA Repair Enzymes
Lung Volume Measurements
Nucleic Acid Regulatory Sequences
Guanine
Virus Diseases
Respiratory Tract Infections
Histones
Extracellular Matrix
Oxidative Stress
Chronic Disease
Asthma
Quality of Life
Viruses
Morbidity
DNA

Keywords

  • 8-oxoguanine DNA glycosylase (OGG1)
  • Airway remodeling
  • Bromodomain-containing protein 4 (BRD4)
  • Epigenetics
  • Mesenchymal transition
  • Myofibroblast

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Targeting inducible epigenetic reprogramming pathways in chronic airway remodeling. / Brasier, Allan R.; Boldogh, Istvan.

In: Drugs in Context, Vol. 8, 2019-8-3, 01.01.2019.

Research output: Contribution to journalReview article

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