Topological and geometric analysis of cell states in single-cell transcriptomic data

Single-cell RNA sequencing (scRNA-seq) enables dissecting cellular heterogeneity in tissues, resulting in numerous biological discoveries. Various computational methods have been devised to delineate cell types by clustering scRNA-seq data, where clusters are often annotated using prior knowledge of marker genes. In addition to identifying pure cell types, several methods have been developed to identify cells undergoing state transitions, which often rely on prior clustering results. The present computational approaches predominantly investigate the local and first-order structures of scRNA-seq data using graph representations, while scRNA-seq data frequently display complex high-dimensional structures. Here, we introduce scGeom, a tool that exploits the multiscale and multidimensional structures in scRNA-seq data by analyzing the geometry and topology through curvature and persistent homology of both cell and gene networks. We demonstrate the utility of these structural features to reflect biological properties and functions in several applications, where we show that curvatures and topological signatures of cell and gene networks can help indicate transition cells and the differentiation potential of cells. We also illustrate that structural characteristics can improve the classification of cell types.