Multiomic Characterization of DNA Released after Airway Exposure to Allergens and Nanoparticles Reveals Selective Export of Repetitive and Fragile Site DNA

Allergen and nanoparticle exposure generate reactive oxygen species (ROS) that endanger genome integrity, yet airway epithelial cells survive repeated exposures. Here we show that environmental allergens from Alternaria alternata and polyethyleneimine (PEI) nanoparticles induce oxidative stress, triggering the rapid release of double-stranded DNA fragments enriched for repetitive elements (SINEs, LINEs, and LTRs), centromeric sequences, and late-replicating, origin-poor fragile site-containing genes. Nanopore sequencing, along with a multiomics approach, was used to analyze fragments of extracellular DNA (eDNA) in human and mouse airway epithelial cells and bronchoalveolar lavage fluid from mice. We show that eDNA release following Alternaria or PEI exposure produces similar genomic sequence profiles, suggesting that a mechanism exists to selectively export these fragments out of the nucleus and into the airway lumen. However, epigenomic modifications localized around transcriptionally active regions differed between Alternaria and PEI exposures, with potentially lasting implications for gene expression and function in airway epithelia. We propose that export of DNA fragments is selective to reduce repetitive DNA fragment accumulation and secondary structure formation in the nucleus, thus ensuring airway epithelial cell survival.NEW & NOTEWORTHY Exposure of airway epithelia to environmental allergens or nanoparticles invokes a novel genome-protective physiological response to oxidative stress. Fragments of double-stranded genomic DNA released into the airway lumen originate from repetitive, transcriptionally active, and fragile sites within the genome. Exporting DNA with high repetitive content potentially aids cell survival through the preservation of genome integrity and fidelity during the repair process.