Asma

Current perspectives

Environmental epigenetics of asthma: An update
Shuk-Mei Ho, PhD Cincinnati, Ohio

Asthma, a chronic inflammatory disorder of the airway, is influenced by interplay between genetic and environmental factors now known to be mediated by epigenetics. Aberrant DNA methylation, altered histone modifications, specific microRNA expression, and other chromatin alterationsorchestrate a complex early-life reprogramming of immune T-cell response, dendritic cell function, macrophage activation, and a breach of airway epithelial barrier that dictates asthma risk and severity in later life. Adult-onset asthma is under analogous regulation. The sharp increase in asthma prevalence over the past 2 or 3 decades and the large variations among populations of similar racial/ethnicbackground but different environmental exposures favors a strong contribution of environmental factors. This review addresses the fundamental question of whether environmental influences on asthma risk, severity, and steroid resistance are partly due to differential epigenetic modulations. Current knowledge on the epigenetic effects of tobacco smoke, microbial allergens, oxidants, airborne particulatematter, diesel exhaust particles, polycyclic aromatic hydrocarbons, dietary methyl donors and other nutritional factors, and dust mites is discussed. Exciting findings have been generated by rapid technological advances and well-designed experimental and population studies. The discovery and validation of epigenetic biomarkers linked to exposure, asthma, or both might lead to better epigenotyping ofrisk, prognosis, treatment prediction, and development of novel therapies. (J Allergy Clin Immunol 2010;126:453-65.) Key words: Pulmonary disorder, traffic-related pollutants, polycyclic aromatic hydrocarbons, microbial and viral infection, lipopolysaccharide, endotoxin, oxidant early-life programming, nutrition, maternal exposure, TH cells, dendritic cells, macrophages, lung epithelial cells,phenotype plasticity, developmental basis of disease, gene-environment interaction, DNA methylation, histone modification, microRNA, chromatin remodeling, allergen, inflammatory response

Abbreviations used ACSL3: Acyl-CoA synthetase long-chain family member 3 AXL: AXL receptor tyrosine kinase BaP: Benzo[a]pyrene DC: Dendritic cell DEP: Diesel exhaust particle DNMT: DNA methyltransferase ETS:Environmental tobacco smoke Foxp3: Forkhead box protein 3 HAT: Histone acetyltransferase HDAC: Histone deacetylase IL: Interleukin MAOB: Monoamine oxidase type B miRNA: MicroRNA NF-kB: Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 PAH: Polycyclic aromatic hydrocarbon PM: Particulate matter PTPRO: Protein tyrosine phosphatase, receptor type, O TLR: Toll-like receptor TSA:Trichostatin A

complex disease for which a subject’s risk is believed to be determined by a complicated interplay of one’s genetics and environmental exposures. The genetic1 or environmental2 explanations of asthma have been discussed and debated for many years. Our recent understanding of epigenetics as a mechanism mediating gene-environment interaction offers new opportunities to advance novel conceptsand re-examine established ones about this disease.3,4 In this review I will first discuss some key features of asthma, the basic principles of epigenetic regulation, and theories of phenotype/developmental plasticity before summarizing recent advances in environmental epigenetics that influence asthma pathogenesis. I will address future challenges and opportunities for the field, focusing on thosethat might help prevent asthma.

Asthma is still poorly understood. It is not one disease but many, with some known but many unidentifiable causes underlying its development and manifestation. As such, it is referred to as a
From the Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati College of Medicine. Supported by National Institutes of Health...