TY - JOUR T1 - Nonparametric Bayesian inference of transcriptional branching and recombination identifies regulators of early human germ cell development JF - bioRxiv DO - 10.1101/167684 SP - 167684 AU - Christopher A. Penfold AU - Anastasiya Sybirna AU - John Reid AU - Yun Huang AU - Lorenz Wernisch AU - Zoubin Ghahramani AU - Murray Grant AU - M. Azim Surani Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/07/24/167684.abstract N2 - 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 may be reversible, particularly during the onset of disease, exemplifying a recombination process. Single cell transcriptomics provide a rich resource to explore the temporal progression of bifurcations in gene activity, and thus elucidate 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 BRGPs 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 and genetic regulators. By concentrating on the earliest 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. ER -