Systematic identification of cell fate regulatory programs using a single-cell atlas of mouse development

Single-cell genomics is altering our understanding of the Waddington landscape, and provides a more general representation of the state manifold. Yet, the molecular regulations behind the state manifold remain poorly understood. We construct a dynamic cell landscape of mouse lineage differentiation at the single-cell level and thereby reveal both lineage-common and lineage-specific regulatory programs during cell type maturation. We verify lineage-common regulatory programs that are universal during the development of invertebrates and vertebrates. In particular, we identify Xbp1 as an evolutionarily conserved regulator of cell fate determinations across different species. We demonstrate that Xbp1 transcriptional regulation is important for the stabilization of the genetic network for a wide range of cell types. Our results offer genetic and molecular insights into the cell fate decisions and provide resources to advance the understanding of cellular state manifolds.