SingleCellGGM enables gene expression program identification from single-cell transcriptomes and facilitates universal cell label transfer.

Gene co-expression analysis of single-cell transcriptomes, aiming to define functional relationships between genes, is challenging due to excessive dropout values. Here, we developed a single-cell graphical Gaussian model (SingleCellGGM) algorithm to conduct single-cell gene co-expression network analysis. When applied to mouse single-cell datasets, SingleCellGGM constructed networks from which gene co-expression modules with highly significant functional enrichment were identified. We considered the modules as gene expression programs (GEPs). These GEPs enable direct cell-type annotation of individual cells without cell clustering, and they are enriched with genes required for the functions of the corresponding cells, sometimes at levels greater than 10-fold. The GEPs are conserved across datasets and enable universal cell-type label transfer across different studies. We also proposed a dimension-reduction method through averaging by GEPs for single-cell analysis, enhancing the interpretability of results. Thus, SingleCellGGM offers a unique GEP-based perspective to analyze single-cell transcriptomes and reveals biological insights shared by different single-cell datasets.