Journal Article

Accurate Spatial Heterogeneity Dissection and Gene Regulation Interpretation for Spatial Transcriptomics using Dual Graph Contrastive Learning

Wong, Ka‐Chun, Yu, Zhuohan, Yang, Yuning, Zhang, Zhaolei, Li, Xiangtao, Zhao, Yuming, Chen, Xingjian

2025

Overview

Recent advances in spatial transcriptomics have enabled simultaneous preservation of high‐throughput gene expression profiles and the spatial context, enabling high‐resolution exploration of distinct regional characterization in tissue. To effectively understand the underlying biological mechanisms within tissue microenvironments, there is a requisite for methods that can accurately capture external spatial heterogeneity and interpret internal gene regulation from spatial transcriptomics data. However, current methods for region identification often lack the simultaneous characterizing of spatial structure and gene regulation, thereby limiting the ability of spatial dissection and gene interpretation. Here, stDCL is developed, a dual graph contrastive learning method to identify spatial domains and interpret gene regulation in spatial transcriptomics data. stDCL adaptively incorporates gene expression data and spatial information via a graph embedding autoencoder, thereby preserving critical information within the latent embedding representations. In addition, dual graph contrastive learning is proposed to train the model, ensuring that the latent embedding representation closely resembles the actual spatial distribution and exhibits cluster similarity. Benchmarking stDCL against other state‐of‐the‐art clustering methods using complex cortex datasets demonstrates its superior accuracy and effectiveness in identifying spatial domains. Our analysis of the imputation matrices generated by stDCL reveals its capability to reconstruct spatial hierarchical structures and refine differential expression assessment. Furthermore, it is demonstrated that the versatility of stDCL in interpretability of gene regulation, spatial heterogeneity at high resolution, and embryonic developmental patterns. In addition, it is also showed that stDCL can successfully annotate disease‐associated astrocyte subtypes in Alzheimer's disease and unravel multiple relevant pathways and regulatory mechanisms. stDCL, a dual graph contrastive learning method, captures spatial heterogeneity and interprets gene regulation in spatial transcriptomics data. Integrating spatial and gene expression data through graph embeddings, stDCL provides robust spatial characterization and accurate region identification, reconstructs spatial hierarchies, and identifies disease‐associated cell subtypes, unveiling new insights into tissue microenvironments and disease mechanisms.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Animals / Clustering / Datasets / dual graph contrastive learning / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation - genetics / gene regulation / graph contrastive learning / Humans / Learning / Machine Learning / Mice / Morphology / Pathology / spatial heterogeneity / Transcriptome - genetics