Epitranscriptomic and Epigenetic Loops Driving the Response to Naphthalene

1. PROJECT SUMMARY The goal of the proposed studies is to define the interplay between the epitranscriptome and the epigenome in regulating cellular responses to toxicants, focusing on the respiratory toxicant naphthalene (NA) as one of the most abundant components of wood smoke. Epi-marks in the form of DNA-based epigenetic modifications that regulate transcription and RNA-based epitranscriptomic modifications that regulate translation are vital to exposure responses and human health. We developed epitranscriptomic detection technology and showed that tRNA modifications and tRNA levels “reprogram” as a function of cell stress to cause selective translation of mRNAs enriched with cognate codons read by the reprogrammed tRNAs. In parallel, we showed that synonymous codons are differentially enriched in functional gene families, with reactive oxygen species (ROS)- detoxification and stress-response programs having unique codon usage patterns that can be translationally regulated by specific wobble U- and wobble G-based tRNA modifications. Our studies have also identified genes for epigenetic systems and transcription factors as having distinct codon biases suggestive of translational regulation. We have demonstrated that the Alkbh8 tRNA writer is essential to the acute and tolerizing response to NA, via the regulation of ROS detoxifying selenoproteins. Our mouse findings allow us to predict that at least 4 epitranscriptomic marks and 3 other writers should be regulated in the response to NA in vivo, as well as a host of epigenetic-, transcription- and translation-based regulatory systems. In this study, we propose 4 Aims to test the hypotheses that (1) epitranscriptomic reprogramming is required to respond to acute exposures (NA, wood smoke) and to tolerate and adapt to repeated challenges from toxicants (NA) that cause increased ROS and lung inflammation and (2) that tRNA modifications will translationally regulate specific epigenetic systems to coordinate transcription and stress responses in epitranscriptomic-epigenetic loops. Our mechanistic findings on translational regulation in human cells will be tested using NA and wood smoke exposure in mice and assayed in the blood samples of firefighters exposed to wood smoke in training exercises. Project Number: 1R01ES038107-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Thomas Begley (+1 co-PI) | Institution: STATE UNIVERSITY OF NEW YORK AT ALBANY, ALBANY, NY | Award Amount: $814,154 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 KUDS-N (57)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11280665