By integrating genome-wide association studies loci from Alzheimer's disease, multiple sclerosis, and schizophrenia, scReGAT identifies disease-associated cell types and uncovers candidate regulatory mechanisms underlying complex trait associations, positioning scReGAT as a robust and generalizable framework for decoding long-range gene regulation at single-cell resolution.
Abstract
Understanding gene regulation at single-cell resolution is crucial for unraveling development, disease, and cellular identity. We introduce single-cell regulatory graph attention network (scReGAT), a deep learning framework that integrates prior knowledge of cis-regulatory element (cRE)-gene and transcription factor-gene interactions to reconstruct cell-specific regulatory networks. Central to scReGAT is a knowledge-guided regulatory graph (kRG), which combines experimentally validated regulatory interactions with cell-resolved chromatin accessibility profiles. These graphs serve as the foundation for training a Graph Attention Network (GAT) to predict gene expression and quantify the contribution of specific regulatory interactions using an interpretable regulatory score for each edge. In benchmarking across five single-cell multi-omics datasets, scReGAT successfully recapitulates known cell-type-specific cRE-gene interactions. In both neuroblastoma and osteogenic differentiation systems, it uncovers dynamic regulatory rewiring that predicts transcriptional transitions. Furthermore, by integrating genome-wide association studies loci from Alzheimer's disease, multiple sclerosis, and schizophrenia, scReGAT identifies disease-associated cell types and uncovers candidate regulatory mechanisms underlying complex trait associations. These results position scReGAT as a robust and generalizable framework for decoding long-range gene regulation at single-cell resolution. The source code of scReGAT can be accessed at https://github.com/TianLab-Bioinfo/scReGAT/ and https://ngdc.cncb.ac.cn/biocode/tool/BT008081.
A family of classification models, scE2G, is introduced that predict enhancer–gene regulatory interactions from single-cell datasets and enable mapping of these interactions across diverse cell types and tissues and will enable accurate mapping of enhancer–gene regulatory interactions across thousands of human cell types.
Maya U. Sheth, Wei-Lin Qiu, X. Ma et al.· Nature Genetics· 1 citation
Transcriptional regulation is governed by interactions between cis-regulatory elements (CREs) and trans-acting regulators in a context-specific manner. Although DNA and single-cell foundation models have enabled modeling regulatory biology at scale, most represent either sequence or cellular state alone, limiting their ability to capture context-dependent gene regulation. Here we present RegFM, a context-aware foundation model for human transcriptional regulation. RegFM treats transcriptional regulation as a dialogue between cis-regulatory sequences (e.g., CREs) and trans-acting regulators (e.g., transcription factors (TFs) and chromatin regulators (CRs)) by coupling long-range CRE representations with TFs and CRs activity. Trained on large-scale ENCODE and CELLxGENE transcriptomic profiles, RegFM learns gene-centered regulatory representations that generalize across unseen cellular contexts. In a wide range of tasks, including gene expression prediction, cis-regulatory element annotation, bivalent promoter and dosage-sensitivity classification, and perturbation-response prediction, RegFM consistently improves over existing methods. RegFM emerges as a scalable and interpretable framework for modeling human transcriptional regulation and provides insights into context-dependent gene regulatory programs.
Zijing Gao, Yining Sun, Hao-Chen Wang et al.· bioRxiv· 0 citations
A structure-aware interleaved-attention graph learning framework, termed IAGRN, is proposed for GRN inference from scRNA-seq data that interleaves topology-constrained local attention with distance-aware global attention, enabling effective integration of structural priors and long-range regulatory signals.
Yue Wang, Si-Cheng Tian, Dan Li· International Journal of Mol...· 0 citations
The ScanNet framework is a scalable, transferable, and mechanistically informed framework for accurate cell type annotation across diverse single-cell data modalities and can be flexibly transferred to single-cell ATAC-seq data by mapping chromatin accessibility to gene level.
Yongyu Long, Wenhao Zhang, Lan Cao et al.· PLoS Computational Biology· 0 citations
Gene regulatory network (GRN) inference is an essential tool for revealing dysregulated relationships between genes in different cell types from single-cell transcriptomic (SCT) data. GRNs based on Bayesian networks (BNs) learned from SCT data can elucidate directed regulatory relationships representing complex disease mechanisms and their interplay through graphical modeling. However, software for learning BNs from SCT data is not widely available, nor is software for evaluating the BNs' structural accuracy in representing causal relationships between genes. Here, we describe the scstruc R package. This package provides a suite of BN structure learning algorithms specifically designed to handle SCT data, to evaluate the resulting networks based on the causal relationships they represent regardless of the availability of established molecular interaction networks, and to compare regulatory relationships between conditions. We demonstrated that scstruc can identify biologically relevant differential regulatory relationships between groups on a per-cell basis.
N. Sato, Marco Scutari, S. Imoto· Cell Reports Methods· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.