Enhanced Single-Cell RNA-seq Embedding through Gene Expression and Data-Driven Gene-Gene Interaction Integration

Abstract: Single-cell RNA sequencing (scRNA-seq) provides unprecedented insights into cellular heterogeneity, enabling detailed analysis of complex biological systems at single-cell resolution. However, the high dimensionality and technical noise inherent in scRNA-seq data pose significant analytical challenges. While current embedding methods focus primarily on gene expression levels, they often overlook crucial gene-gene interactions that govern cellular identity and function. To address this limitation, we present a novel embedding approach that integrates both gene expression profiles and data-driven gene-gene interactions. Our method first constructs a Cell-Leaf Graph (CLG) using random forest models to capture regulatory relationships between genes, while simultaneously building a K-Nearest Neighbor Graph (KNNG) to represent expression similarities between cells. These graphs are then combined into an Enriched Cell-Leaf Graph (ECLG), which serves as input for a graph neural network to compute cell embeddings. By incorporating both expression levels and gene-gene interactions, our approach provides a more comprehensive representation of cellular states. Extensive evaluation across multiple datasets demonstrates that our method enhances the detection of rare cell populations and improves downstream analyses such as visualization, clustering, and trajectory inference. This integrated approach represents a significant advance in single-cell data analysis, offering a more complete framework for understanding cellular diversity and dynamics.