Molecular Mechanisms of Epitranscriptomic Dysregulation Induced by Toxic Metals

/Abstract Naturally occurring heavy metals in our environment can be harmful to human health. For instance, arsenic, cadmium, chromium, and nickel are classified as Group 1 carcinogens by the International Agency for Research on Cancer. Post-transcriptional gene regulation—through RNA modifications or regulatory RNAs—is a major mechanism by which cells reprogram gene expression. Our objective is to determine how heavy metals impact RNA modifications and the processing of regulatory RNAs. In Aim 1, we will assess the effects that heavy metals may have on a key mRNA methyltransferase, METTL3-METTL14, evaluating both its enzymatic efficiency and specificity. We will also investigate how a heavy metal influences m6A in the transcriptome and how RNA modification events are linked to changes in chromatin and DNA methylation. In Aim 2, we will evaluate the effects of heavy metals on an oncogenic tRNA methyltransferase, METTL1. We will analyze variations in its activity and specificity with different metals and will also explore any crosstalk between METTL1 activity and other tRNA modifications, along with AKT signaling that phosphorylates METTL1. In Aim 3, we will study the effects of heavy metals on microRNA biogenesis. The Drosha-DGCR8 complex depends on multiple metals to initiate microRNA processing. We will examine the mechanisms that underlie metal-induced dysregulation of microRNA processing. Additionally, we will analyze how heavy metals affect the crosstalk between RNA methylation and processing. In summary, our work will leverage the latest insights into the molecular mechanisms of catalysis and substrate specificity of RNA modification and processing enzymes to provide new information on how heavy metal toxins interact with our epitranscriptome to induce pathogenesis. Project Number: 1R01ES038329-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Yunsun Nam | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $649,193 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 KUDS-N (57)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11290098