Analysis of Single-Cell Gene Pair Coexpression Landscapes by Stochastic Kinetic Modeling Reveals Gene-Pair Interactions in Development

Abstract

Single-cell transcriptomics is advancing discovery of the molecular determinants of cell identity, while spurring development of novel data analysis methods. Stochastic mathematical models of gene regulatory networks help unravel the dynamic, molecular mechanisms underlying cell-to-cell heterogeneity, and can thus aid interpretation of heterogeneous cell-states revealed by single-cell measurements. However, integrating stochastic gene network models with single cell data is challenging. Here, we present a method for analyzing single-cell gene-pair coexpression patterns, based on biophysical models of stochastic gene expression and interaction dynamics. We first developed a high-computational-throughput approach to stochastic modeling of gene-pair coexpression landscapes, based on numerical solution of gene network Master Equations. We then comprehensively catalogued coexpression patterns arising from tens of thousands of gene-gene interaction models with different biochemical kinetic parameters and regulatory interactions. From the computed landscapes, we obtain a low-dimensional “shape-space” describing distinct types of coexpression patterns. We applied the theoretical results to analysis of published single cell RNA sequencing data and uncovered complex dynamics of coexpression among gene pairs during embryonic development. Our approach provides a generalizable framework for inferring evolution of gene-gene interactions during critical cell-state transitions.