Acetaldehyde-driven mRNA methylation and expression changes in ethanol-metabolizing enzyme genes

This study examines how the alcohol metabolite acetaldehyde modulates mRNA methylation and expression of ethanol-metabolizing genes, uncovering its epigenetic role in ethanol metabolism. Using neuron-like (SH-SY5Y) and non-neuronal (SW620) cellular models, we examined the effects of chronic intermittent acetaldehyde (CIA) exposure and subsequent withdrawal (CIA+WD) on global RNA m6A modifications and the methylation and expression of three brain ethanol-metabolizing genes: <i>CAT</i> (catalase), <i>CYP2E1</i> (cytochrome P450 2E1), and <i>ALDH2</i> (aldehyde dehydrogenase 2). A 3-week CIA exposure, with or without 24-hour withdrawal, did not significantly alter global m6A methylation levels in either cell line. However, acetaldehyde exposure/withdrawal induced hypermethylation at the mRNA stop codon regions of <i>ALDH2</i> (CIA: <i>p</i> = 0.002; CIA+WD: <i>p</i> = 0.055) and <i>CAT</i> (CIA: <i>p</i> = 0.077; CIA+WD: <i>p</i> = 0.036) in SH-SY5Y cells, but not in SW620 cells. Furthermore, <i>ALDH2</i> mRNA expression was significantly upregulated in both cell types following exposure (SH-SY5Y: <i>p</i> = 0.073 [CIA] and 0.00002 [CIA+WD]; SW620: <i>p</i> = 0.0009 [CIA] and 0.00008 [CIA+WD]). In contrast, <i>CYP2E1</i> mRNA methylation and the expression of <i>CYP2E1</i> and <i>CAT</i> remained unchanged. These findings highlight the cell-specific epigenetic effects of acetaldehyde, particularly its role in modulating mRNA methylation and expression of <i>ALDH2</i>, a key enzyme in alcohol metabolism.