Generative modeling of single-cell time series with PRESCIENT enables prediction of cell trajectories with interventions

Existing computational methods that use single-cell RNA-sequencing (scRNA-seq) for cell fate prediction do not model how cells evolve stochastically and in physical time, nor can they predict how differentiation trajectories are altered by proposed interventions. We introduce PRESCIENT (Potential eneRgy undErlying Single Cell gradIENTs), a generative modeling framework that learns an underlying differentiation landscape from time-series scRNA-seq data. We validate PRESCIENT on an experimental lineage tracing dataset, where we show that PRESCIENT is able to predict the fate biases of progenitor cells in hematopoiesis when accounting for cell proliferation, improving upon the best-performing existing method. We demonstrate how PRESCIENT can simulate trajectories for perturbed cells, recovering the expected effects of known modulators of cell fate in hematopoiesis and pancreatic β cell differentiation. PRESCIENT is able to accommodate complex perturbations of multiple genes, at different time points and from different starting cell populations, and is available at https://github.com/gifford-lab/prescient.

Redistribution of FLAgellar Member 8 during the trypanosome life cycle: consequences for cell fate prediction

The single flagellum of African trypanosomes is essential in multiple aspects of the parasite development. The FLAgellar Member 8 protein (FLAM8), localised to the tip of the flagellum in cultured insect forms, was identified as a marker of the locking event that controls flagellum length. Here, we investigated whether FLAM8 could also reflect the flagellum maturation state in other stages. We observed that FLAM8 distribution extended along the entire flagellar cytoskeleton in mammalian infective forms. Then, a rapid FLAM8 concentration to the distal tip occurs during differentiation into early insect forms, illustrating for the first time the remodeling of an existing flagellum in trypanosomes. In the tsetse cardia, FLAM8 further localizes to the entire length of the new flagellum during an asymmetric division. Strikingly, in parasites dividing in the tsetse midgut and in the salivary glands, the amount and distribution of FLAM8 in the new flagellum was seen to predict the daughter cell fate. We propose and discuss how FLAM8 could be considered as a meta-marker of the flagellum stage and maturation state in trypanosomes.Summary statementThe trypanosome protein FLAM8 displays a dynamic and stage-specific distribution during the entire parasite cycle, representing a novel marker of the flagellum stage and maturation state.