Structure-aware deep learning enhances m6A prediction and reveals cell type-associated RNA structural signatures

N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays essential roles in gene regulation and disease pathogenesis. Computational prediction of m6A sites offers a scalable alternative to costly experimental approaches, yet current methods rely predominantly on linear sequence features. This overlooks potentially informative RNA structural context, which is associated with local methylation patterns and may provide complementary predictive information beyond linear sequence motifs. To incorporate this complementary information, we propose SMART-m6A (Sequence-structure Multifeature Attention RNA Transformer for m6A), a deep learning framework that integrates sequence and structural information through parallel convolutional feature extraction and structure-guided attention for multifeature fusion. SMART-m6A achieves superior predictive performance compared to existing methods, with particularly clear advantages in sequence-ambiguous candidates. Beyond prediction accuracy, learned attention patterns reveal strong concordance with experimentally validated m6A-binding protein recognition sites and identify potentially novel regulatory motifs. Through systematic ablation studies and targeted structural-input perturbation analyses, we show that sequence and structure provide complementary predictive information, and that sites with greater prediction sensitivity to structural perturbation exhibit distinct local structural profiles between cell lines. Collectively, this work demonstrates the predictive value of sequence-derived structural features in m6A modeling and provides a multifeature deep learning framework for accurate and interpretable structure-aware epitranscriptomic prediction.

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Publication Details

Journal
PLoS Computational Biology
Published
2026-08-14
DOI
https://doi.org/10.1371/journal.pcbi.1014649
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Structure-aware deep learning enhances m6A prediction and reveals cell type-associated RNA structural signatures

Yihan Lin, Zhiyuan Li, Mingze Sun, Di Zhang
PLoS Computational Biology
RNA modifications and cancer
article

Structure-aware deep learning enhances m6A prediction and reveals cell type-associated RNA structural signatures

Yihan Lin, Zhiyuan Li, Mingze Sun, Di Zhang
article en

Abstract

N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays essential roles in gene regulation and disease pathogenesis. Computational prediction of m6A sites offers a scalable alternative to costly experimental approaches, yet current methods rely predominantly on linear sequence features. This overlooks potentially informative RNA structural context, which is associated with local methylation patterns and may provide complementary predictive information beyond linear sequence motifs. To incorporate this complementary information, we propose SMART-m6A (Sequence-structure Multifeature Attention RNA Transformer for m6A), a deep learning framework that integrates sequence and structural information through parallel convolutional feature extraction and structure-guided attention for multifeature fusion. SMART-m6A achieves superior predictive performance compared to existing methods, with particularly clear advantages in sequence-ambiguous candidates. Beyond prediction accuracy, learned attention patterns reveal strong concordance with experimentally validated m6A-binding protein recognition sites and identify potentially novel regulatory motifs. Through systematic ablation studies and targeted structural-input perturbation analyses, we show that sequence and structure provide complementary predictive information, and that sites with greater prediction sensitivity to structural perturbation exhibit distinct local structural profiles between cell lines. Collectively, this work demonstrates the predictive value of sequence-derived structural features in m6A modeling and provides a multifeature deep learning framework for accurate and interpretable structure-aware epitranscriptomic prediction.

PLoS Computational BiologyVol. 22(8)
University of Electronic Science and Technology of China (CN), Peking University (CN), Center for Life Sciences (CN)
National Natural Science Foundation of China, Ministry of Education of the People's Republic of China, National Key Research and Development Program of China
Openalex Percentile: Top 16%
RNA modifications and cancer
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