Understanding YTHDF2-mediated mRNA Degradation By m⁶A-BERT-Deg

N6-methyladenosine (m⁶A) is the most abundant mRNA modification within mammalian cells, holding pivotal significance in the regulation of mRNA stability, translation, and splicing. Furthermore, it plays a critical role in the regulation of RNA degradation by primarily recruiting the YTHDF2 reader protein. However, the selective regulation of mRNA decay of the m⁶A-methylated mRNA through YTHDF2 binding is poorly understood. To improve our understanding, we developed m⁶A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated degradation of m⁶A-methylated mRNAs. We meticulously assembled a high-quality training dataset by integrating multiple data sources for the HeLa cell line. To overcome the limitation of small training samples, we employed a pre-training-fine-tuning strategy by first performing a self-supervised pre-training of the model on 427,760 unlabeled m⁶A site sequences. The test results demonstrated the importance of this pre-training strategy in enabling m⁶A-BERT-Deg to outperform other benchmark models. We further conducted a comprehensive model interpretation and revealed a surprising finding that the presence of co-factors in proximity to m⁶A sites may disrupt YTHDF2-mediated mRNA degradation, subsequently enhancing mRNA stability. We also extended our analyses to the HEK293 cell line, shedding light on the context-dependent YTHDF2-mediated mRNA degradation.