Dynamical information enables inference of gene regulation at single-cell scale

Abstract

Cell dynamics and biological function are governed by intricate networks of molecular interactions. Inferring these interactions from data is a notoriously difficult inverse problem. The majority of existing network inference methods work at the population level to construct population-averaged representations of gene interaction networks, and thus do not naturally allow us to infer differences in gene regulation activity across heterogeneous cell populations. We introduce locaTE, an information theoretic approach that leverages single cell dynamical information together with geometry of the cell state manifold to infer cell-specific, causal gene interaction networks in a manner that is agnostic to the topology of the underlying biological trajectory. We find that factor analysis can give detailed insights into the inferred cell-specific GRNs. Through extensive simulation studies and applications to three experimental datasets spanning mouse primitive endoderm formation, pancreatic development, and haematopoiesis, we demonstrate superior performance and the generation of additional insights compared to standard static GRN inference methods. We find that locaTE provides a powerful, efficient and scalable network inference method that allows us to distill cell-specific networks from single cell data. Graphical abstractCell-specific network inference from estimated dynamics and geometry LocaTE takes as input a transition matrix P that encodes inferred cellular dynamics as a Markov chain on the cell state manifold. By considering the coupling (X{tau}, X-{tau}), locaTE produces an estimate of transfer entropy for each cell i and each pair of genes (j, k). Downstream factor analyses can extract coherent patterns of interactions in an unsupervised fashion. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/523176v4_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@12dc737org.highwire.dtl.DTLVardef@722a08org.highwire.dtl.DTLVardef@1258a03org.highwire.dtl.DTLVardef@1880a1e_HPS_FORMAT_FIGEXP M_FIG C_FIG