Integrating scRNA-seq and scATAC-seq with inter-type attention heterogeneous graph neural networks

Single-cell multi-omics techniques, which enable the simultaneous measurement of multiple modalities such as RNA gene expression and Assay for Transposase-Accessible Chromatin (ATAC) within individual cells, have become a powerful tool for deciphering the intricate complexity of cellular systems. Most current methods rely on motif databases to establish cross-modality relationships between genes from RNA-seq data and peaks from ATAC-seq data. However, these approaches are constrained by incomplete database coverage, particularly for novel or poorly characterized relationships. To address these limitations, we introduce single-cell Multi-omics Integration (scMI), a heterogeneous graph embedding method that encodes both cells and modality features from single-cell RNA-seq and ATAC-seq data into a shared latent space by learning cross-modality relationships. By modeling cells and modality features as distinct node types, we design an inter-type attention mechanism to effectively capture long-range cross-modality interactions between genes and peaks. Benchmark results demonstrate that embeddings learned by scMI preserve more biological information and achieve comparable or superior performance in downstream tasks including modality prediction, cell clustering, and gene regulatory network inference compared to methods that rely on databases. Furthermore, scMI significantly improves the alignment and integration of unmatched multi-omics data, enabling more accurate embedding and improved outcomes in downstream tasks.