Tissue-specific mRNA m6A reprogramming unveils vitamin-driven post-transcriptional regulation in mice.

Vitamins are essential metabolic cofactors, yet their roles in epitranscriptomic regulation, particularly N 6-methyladenosine (m6A) modification, remain unclear. Here, we investigate the effects of various vitamins (VB2, VB6, and VB12) on the mRNA m6A epitranscriptome in multiple mouse tissues (brain, liver, and testis). Clustering analyses reveal closer similarity between the brain and testis m6A profiles, whereas the liver exhibits a unique pattern, reflecting tissue-specific regulatory dynamics. More than 90% of m6A sites are independent of mRNA abundance, highlighting the post-transcriptional role of m6A modification. Additionally, alternative splicing (AS) variations reveal complex interactions between vitamins, m6A modification, and AS, with tissue- and vitamin-specific effects on biological pathways. We identify 22 comethylation modules, associated with pathways such as neurodegenerative diseases and immune regulation. Key vitamin-responsive genes are found as central regulators of m6A dynamics, aligning with known roles of vitamins in metabolism, neural plasticity, and gene expression. Together, our findings provide the first comprehensive atlas of vitamin-driven, tissue-specific m6A modifications, offering new insights into the post-transcriptional regulatory mechanisms underlying vitamin-mediated cellular functions and their implications for nutritional or pharmacological modulation of the epitranscriptome in health and disease.