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

Abstract Waddington’s epigenetic landscape is an abstract metaphor frequently used to explain cell fate decisions. Recent advances in single-cell genomics are altering our understanding of the Waddington landscape. Yet, the molecular regulations behind 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 regulatoryprograms 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 gene regulatory programs systematically and provide resources to advance the understanding of the cell fate decisions.