Linking environmental exposures to molecular regulation of inflammation via epigenetic histone signatures in an exacerbation prone pediatric asthma cohort

Abstract

Abstract Environmental exposures, such as air pollution, are correlated with asthma susceptibility and airway inflammation. Epigenetic mechanisms can translate these exposures to regulation of molecular pathways that drive asthma pathogenesis. Indeed, specific epigenetic modifications have been linked to regulation of asthma-associated inflammation. Yet, there have been no studies linking environmental exposures to direct regulation of molecular mechanisms driving dysfunction of inflammation in pediatric asthma. Here we examined a cohort of exacerbation prone pediatric asthmatics tracking exposure through multiple air monitoring methods, including personalized vest monitors, stationary monitors, and Colorado DPHE monitors. We performed ChIP-seq examining histone modifications in PBMCs and integrated the epigenetic data with the environmental exposure data from the air pollution monitors. Our results statistically linked specific histone modifications in PBMCs to specific types of environmental exposures within the pediatric asthmatics. Annotation of these histone modifications to proximal genes identified a potential immune program regulating asthma inflammation. Concomitant examination of the PBMC transcriptome enabled functional analysis of epigenetic regulation of these immune genes. The resultant molecular profiles can be used to identify biomarkers for patient stratification and disease course prediction. Moreover, these studies identify a potential link between the molecular programming associated with environmental exposures and regulation of key biological pathways, which alter immune cell activity that ultimately can increase asthma exacerbation in children.