Inferring extrinsic factor-dependent single-cell transcriptome dynamics using a deep generative model

RNA velocity estimation helps elucidate temporal changes in the single-cell transcriptome. However, current methodologies for inferring single-cell transcriptome dynamics ignore extrinsic factors, such as experimental conditions and neighboring cell. Here, we propose ExDyn—a deep generative model integrated with splicing kinetics for estimating cell state dynamics dependent on extrinsic factors. ExDyn enables the counterfactual inference of cell state dynamics under different conditions. Among the extrinsic factors, ExDyn can extract key features which have large effects on cell state dynamics. ExDyn correctly estimated the difference in dynamics between two conditions and showed better accuracy over existing RNA velocity methods. ExDyn were utilized for unveiling the effect of PERK-knockout on neurosphere differentiation, hematopoietic stem cell differentiation driven by chromatin activity and the dynamics of squamous cell carcinoma cells dependent on colocalized neighboring cells. These results demonstrated that ExDyn is useful for analyzing key features in the dynamic generation of heterogeneous cell populations.