Inferring Gene Regulatory Networks From Single‐Cell RNA Sequencing Data by Dual‐Role Graph Contrastive Learning

RegGAIN is a novel and powerful deep learning framework for inferring gene regulatory networks (GRNs) from single‐cell RNA sequencing data. By integrating self‐supervised contrastive learning with dual‐role gene representations, it consistently outperforms existing methods in both accuracy and robustness. Moreover, RegGAIN effectively uncovers GRN rewiring, enabling the discovery of condition‐specific and dynamic regulatory programs across diverse biological contexts. Abstract Gene regulatory network (GRN) inference is fundamental to understanding the regulatory architecture underlying cellular processes. Accurate reconstruction of cell‐type‐specific GRNs is therefore essential for elucidating the mechanisms that govern cellular identity, development, and disease. However, inferring GRNs from single‐cell RNA sequencing data remains challenging due to data sparsity, noise, and the intrinsic complexity of gene regulation. Here, RegGAIN is presented, a novel deep learning‐based model designed to infer GRNs from single‐cell transcriptomic data. RegGAIN employs self‐supervised contrastive learning to maximize consistency of gene embeddings across perturbed graph views. To characterize regulatory directionality and capture the distinct regulator‐ and target‐driven patterns simultaneously, it leverages separate encoders to learn dual‐role representations for each gene. Comprehensive evaluations demonstrate that RegGAIN achieves accurate and robust GRN reconstruction, consistently outperforming existing methods. The biological relevance of the predicted regulatory interactions is further validated using external epigenetic data. Moreover, RegGAIN enables the discovery of GRN rewiring, revealing condition‐specific and temporally dynamic regulatory programs. Together, RegGAIN offers a powerful and generalizable framework for GRN inference, paving the way for deeper insights into cellular regulation across diverse biological contexts. RegGAIN is a novel and powerful deep learning framework for inferring gene regulatory networks (GRNs) from single-cell RNA sequencing data. By integrating self-supervised contrastive learning with dual-role gene representations, it consistently outperforms existing methods in both accuracy and robustness. Moreover, RegGAIN effectively uncovers GRN rewiring, enabling the discovery of condition-specific and dynamic regulatory programs across diverse biological contexts. Abstract Gene regulatory network (GRN) inference is fundamental to understanding the regulatory architecture underlying cellular processes. Accurate reconstruction of cell-type-specific GRNs is therefore essential for elucidating the mechanisms that govern cellular identity, development, and disease. However, inferring GRNs from single-cell RNA sequencing data remains challenging due to data sparsity, noise, and the intrinsic complexity of gene regulation. Here, RegGAIN is presented, a novel deep learning-based model designed to infer GRNs from single-cell transcriptomic data. RegGAIN employs self-supervised contrastive learning to maximize consistency of gene embeddings across perturbed graph views. To characterize regulatory directionality and capture the distinct regulator- and target-driven patterns simultaneously, it leverages separate encoders to learn dual-role representations for each gene. Comprehensive evaluations demonstrate that RegGAIN achieves accurate and robust GRN reconstruction, consistently outperforming existing methods. The biological relevance of the predicted regulatory interactions is further validated using external epigenetic data. Moreover, RegGAIN enables the discovery of GRN rewiring, revealing condition-specific and temporally dynamic regulatory programs. Together, RegGAIN offers a powerful and generalizable framework for GRN inference, paving the way for deeper insights into cellular regulation across diverse biological contexts. Advanced Science, EarlyView.