Tracing early mammalian lineage decisions by single cell genomics. (360G-Wellcome-105031_D_14_Z)

Lewis Wolpert famously called gastrulation the most important time in your life. During this fascinating process, a pluripotent stem cell population in the early embryo gives rise to the three germ layers from which all organ systems develop. Cell signalling and transcriptional networks are known to regulate aspects of gastrulation, but the precise mechanisms have not been investigated at the single cell level. Thus, new principles remain to be discovered that govern the exit from na ve pluripot ency, epigenetic priming, stochasticity in transcriptional programmes, symmetry breaking, and acquisition of heritable transcriptome patterns. We have brought together a consortium of experts in single cell genomics, mammalian postimplantation development, and computational biology to comprehensively tackle this challenge. We will apply recently established single cell genomics techniques for DNA, RNA, and DNA methylation to profile the majority of the cells in mouse postimplantation embryos. Th is will result in epigenetic and gene expression maps of most cells together with experimentally determined lineage relationships, hence populating a Waddingtonian landscape. Based on such maps, combinations of transcription factors and epigenetic modifiers will be used to experimentally direct differentiation in human iPS cells.