Decoding gene regulation in the mouse embryo using single-cell multi-omics

During embryonic development, transcription-factor mediated remodelling of the epigenome is thought to precede changes in gene expression and prime cells for developmental trajectories. Yet, a comprehensive map of such epigenetic changes is lacking, as are the underlying gene regulatory networks. Here we generate a multi-omics atlas of mouse early organogenesis by simultaneously profiling gene expression and chromatin accessibility from tens of thousands of single cells. We develop a computational method to leverage the multi-modal readouts to predict transcription factor binding events in cis-regulatory elements, which we then use to infer gene regulatory networks that underpin lineage commitment events. Finally we show that these in silico transcription factor binding sites and gene regulatory networks can be used to predict the effect of transcription factor perturbation experiments. We demonstrate this by showing that Brachyury is essential for priming neuromesodermal progenitors into somitic mesoderm fate, which we then validate using embryonic Brachyury knockout. Overall design: 11 samples taken from a time course of mouse embryonic development from E7.5 to E8.75. Includes 10 wildtype and 1 brachyury knockout. Processed using 10x Genomics Multiome kit to produce parallel snRNA-seq and snATAC-seq