Multi-model biological and sequence information fusion for gene regulatory network inference from single-cell transcriptomics

Abstract Identification of transcription factor–target gene interactions and construction of the gene regulatory networks (GRNs) are essential for understanding the molecular mechanisms underlying transcriptional gene regulation. Large-scale single-cell transcriptomics across different tissues offers unprecedented resolution of cellular diversity and regulatory dynamics by capturing gene expression heterogeneity. However, existing methods often lack effective multimodal integration and fail to fully exploit the hierarchical structure in Gene Ontology (GO) and gene sequence level representations, which limits their ability for predictive performance and biological interpretability. We present scMGFGRN, a multi-model deep learning framework that integrates single-cell transcriptomic profiles with gene functional hierarchical relationships, gene sequences by leveraging denoising auto-encoders, graph attention feature extraction and pertained DNA language model to capture multi-source dependencies within multi-model biological knowledge, while its gated multi-head attention module effectively identifies informative regulatory signatures and integrate complementary features from different sources to predict accurate gene regulatory networks. Benchmarking on the seven datasets of human and mouse demonstrates that scMGFGRN out-performs state-of-the-art methods in identifying GRNs. Further analyses reveal that scMGFGRN effectively identifies novel TF– gene interactions (TGIs) and reconstructs cell-type-specific GRNs. Interpretability analysis reveals the contribution patterns of heterogeneous biological sources, demonstrating the ability of scMGFGRN to integrate transcriptomic profiles with multi-model structure information.