Spatially varying gene regulation network inference from spatial transcriptomics.

Motivation: Gene regulatory networks (GRNs) govern cellular functions by coordinating gene expression programs. These regulatory relationships are strongly shaped by local microenvironments, giving rise to dynamic, spatially varying regulatory patterns across tissues. Therefore, it is crucial to infer GRNs at higher, cell-specific resolution while jointly modeling spatial context. However, most existing GRN inference approaches focus on cell-type-level networks or infer cell-specific GRNs without incorporating neighborhood and positional information. Results: We propose SVGRN, a deep learning framework for inferring spatially resolved, high-resolution GRNs from spatial transcriptomics data. SVGRN integrates gene expression, regulatory interactions, and spatial coordinates within a structural equation modeling framework implemented by a conditional variational autoencoder, to learn nonlinear, spatially varying regulatory programs in an unsupervised manner. By conditioning on target locations and incorporating neighborhood information, SVGRN refines tissue-level regulation into spot- or cell-specific GRNs. Across simulated datasets, SVGRN consistently outperforms existing methods under diverse and challenging settings. Applications to seqFISH mouse embryo data and Visium human cutaneous squamous cell carcinoma and fallopian tube datasets demonstrate that SVGRN captures spatially varying regulatory programs underlying development, tumor progression, and tissue organization, highlighting its robustness and broad applicability. Availability and implementation: The source code and data are available at https://github.com/lyrrrr/SVGRN.