Revealing Dynamic Mechanisms of Cell Fate Decisions From Single-Cell Transcriptomic Data.

Cell fate decisions play a pivotal role in development, but technologies for dissecting them are limited. We developed a multifunction new method, Topographer, to construct a "quantitative" Waddington's landscape of single-cell transcriptomic data. This method is able to identify complex cell-state transition trajectories and to estimate complex cell-type dynamics characterized by fate and transition probabilities. It also infers both marker gene networks and their dynamic changes as well as dynamic characteristics of transcriptional bursting along the cell-state transition trajectories. Applying this method to single-cell RNA-seq data on the differentiation of primary human myoblasts, we not only identified three known cell types, but also estimated both their fate probabilities and transition probabilities among them. We found that the percent of genes expressed in a bursty manner is significantly higher at (or near) the branch point (~97%) than before or after branch (below 80%), and that both gene-gene and cell-cell correlation degrees are apparently lower near the branch point than away from the branching. Topographer allows revealing of cell fate mechanisms in a coherent way at three scales: cell lineage (macroscopic), gene network (mesoscopic), and gene expression (microscopic).