Abstract
During embryonic development, cells undertake a series of cell fate decisions to form a complete organism, epitomising a branching process. In some instances, these decisions are reversible, particularly during the onset of disease, exemplifying a recombination process. Single cell transcriptomics provides a rich resource to explore the temporal progression of bifurcations in gene activity, useful to elucidate the mechanisms of cell fate decisions. However, identification of transcriptional branching or recombination poses a major statistical challenge. Here, we have developed a comprehensive nonparametric Bayesian approach to the inference of branching and recombination, in the form of branch-recombinant Gaussian Processes (B-RGPs). We use B-RGPs to infer transcriptional branching that occurs during early human development as primordial germ cells (PGCs), the precursors of sperm and egg, are specified in the developing embryo. Using our approach, we identify known master regulators of human PGC development, and predict roles for a variety of signalling pathways, as well as transcription factors and epigenetic modifiers. By concentrating on the earliest branched signalling events, we identified an antagonistic role for FGF receptor (FGFR) signalling pathway in the acquisition of competence for human PGC fate. Indeed, the experimental validation of our prediction confirmed that pharmacological blocking of FGFR or its downstream effectors (MEK, PI3K and JAK) enhanced the competency for PGC fate in vitro. Thus, B-RGPs represent a powerful and flexible data-driven approach for dissecting the temporal dynamics of cell fate decisions, providing unique insights into the mechanisms of early embryogenesis.