Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA,15261, USA.
Brief Bioinform. 2024 Mar 27;25(3). doi: 10.1093/bib/bbae170.
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.
N6-甲基腺苷（m6A）是哺乳动物细胞中最丰富的 mRNA 修饰，在调节 mRNA 稳定性、翻译和剪接方面具有关键意义。此外，它通过主要募集 YTHDF2 读取蛋白在调节 RNA 降解中起着关键作用。然而，YTHDF2 结合对 m6A 修饰的 mRNA 降解的选择性调节机制还知之甚少。为了增进我们的理解，我们开发了 m6A-BERT-Deg，这是一个专门为预测 YTHDF2 介导的 m6A 修饰 mRNA 降解而设计的 BERT 模型。我们通过整合 HeLa 细胞系的多个数据源，精心组装了一个高质量的训练数据集。为了克服小训练样本的限制，我们采用了预训练-微调策略，首先在 427760 个未标记的 m6A 位点序列上对模型进行自我监督预训练。测试结果表明，这种预训练策略对于使 m6A-BERT-Deg 优于其他基准模型非常重要。我们进一步进行了全面的模型解释，并发现了一个令人惊讶的发现，即 m6A 位点附近的共因子的存在可能会破坏 YTHDF2 介导的 mRNA 降解，从而增强 mRNA 的稳定性。我们还将分析扩展到 HEK293 细胞系，揭示了 YTHDF2 介导的 mRNA 降解的上下文依赖性。
