Epigenetic regulator function through mouse gastrulation

During ontogeny, proliferating cells become restricted in their fate through the combined action of cell-type specific transcription factors and ubiquitous epigenetic machinery, which recognize universally available histone residues or nucleotides but are nonetheless deployed in a highly context-dependent manner(1,2). The molecular functions of these regulators are generally well understood, but assigning direct developmental roles is hampered by complex mutant phenotypes that often emerge following gastrulation(3,4). Recently, single-cell RNA sequencing (scRNA-seq) and analytical approaches have explored this highly conserved process across numerous model organisms(5–8), including mouse(9–18). To elaborate on these strategies, we investigated a panel of ten essential regulators using a combined zygotic perturbation, scRNA-seq platform where many mutant embryos can be assayed simultaneously to recover robust transcriptional and morphological information. Deeper analysis of central Polycomb Repressive Complex (PRC) 1 and 2 members indicate substantial cooperativity, but distinguishes a PRC2-dominant role in restricting the germline that emerges from gross molecular changes within the initial conceptus. We believe our experimental framework will eventually allow for a fully quantitative view of how cellular diversity emerges using an identical genetic template and from a single totipotent cell.