Understanding YTHDF2-mediated mRNA degradation by m6A-BERT-Deg.

Area of Science:

• Molecular Biology
• Bioinformatics
• RNA Biology

Background:

• N6-methyladenosine (m6A) is the most prevalent mRNA modification in mammals, crucial for regulating mRNA stability, translation, and splicing.
• The YTHDF2 protein primarily mediates m6A-dependent mRNA degradation, but the precise regulatory mechanisms remain unclear.

Purpose of the Study:

• To develop a predictive model for YTHDF2-mediated degradation of m6A-modified mRNAs.
• To elucidate the factors influencing selective mRNA decay in response to m6A modification.

Main Methods:

• Development of m6A-BERT-Deg, a BERT model tailored for predicting YTHDF2-mediated mRNA degradation.
• Creation of a high-quality training dataset from multiple sources for HeLa cells.
• Implementation of a pre-training and fine-tuning strategy using extensive unlabeled m6A site sequences to address limited training data.

Main Results:

• The pre-training strategy significantly improved m6A-BERT-Deg performance compared to benchmark models.
• Model interpretation revealed that co-factors near m6A sites can inhibit YTHDF2 binding, thereby increasing mRNA stability.
• Analyses extended to HEK293 cells demonstrated context-dependent regulation of YTHDF2-mediated mRNA degradation.

Conclusions:

• m6A-BERT-Deg provides a powerful tool for predicting YTHDF2-mediated mRNA decay.
• Co-factor presence near m6A sites represents a novel regulatory mechanism for mRNA stability.
• YTHDF2-mediated mRNA degradation is influenced by cellular context.