Diffusion-based generation of gene regulatory networks from scRNA-seq data with DigNet

A gene regulatory network (GRN) intricately encodes the interconnectedness of identities and functionalities of genes within cells, ultimately shaping cellular specificity. Despite decades of endeavors, reverse engineering of GRNs from gene expression profiling data remains a profound challenge, particularly when it comes to reconstructing cell-specific GRNs that are tailored to precise cellular and genetic contexts. Here, we propose a discrete diffusion generation model, called DigNet, capable of generating corresponding GRNs from high-throughput single-cell RNA sequencing (scRNA-seq) data. DigNet embeds the network generation process into a multistep recovery procedure with Markov properties. Each intermediate step has a specific model to recover a portion of the gene regulatory architectures. It thus can ensure compatibility between global network structures and regulatory modules through the unique multistep diffusion procedure. Furthermore, through iMetacell integration and non-Euclidean discrete space modeling, DigNet is robust to the presence of noise in scRNA-seq data and the sparsity of GRNs. Benchmark evaluation results against more than a dozen state-of-the-art network inference methods demonstrate that DigNet achieves superior performance across various single-cell GRN reconstruction experiments. Furthermore, DigNet provides unique insights into the immune response in breast cancer, derived from differential gene regulation identified in T cells. As an open-source software, DigNet offers a powerful and effective tool for generating cell-specific GRNs from scRNA-seq data.