Abstract

Haematopoiesis represents one of the most tractable models of organ development and cellular differentiation. Transcription factor (TF) proteins have long been recognized as major regulators of blood cell development as well as the subsequent differentiation into the multiple mature haematopoietic lineages. It remains largely unknown however, how individual TFs are integrated into wider transcriptional regulatory networks, and how combinatorial TF interactions within these networks drive lineage specific gene expression programs. We have used single cell expression analysis to capture cells with blood-forming potential at four sequential developmental stages. Using novel computational approaches, we have reconstructed the developmental journey at single cell resolution, which reveals asynchrony of maturation and sequential waves of expression for major regulators. We have then used the single cell expression data to construct a transcriptional regulatory network model, and used mouse embryos and embryonic stem cells to validate several model predictions. Our work therefore demonstrates that single cell analysis of a developing organ coupled with novel computational approaches can reveal the transcriptional programs that control organogenesis.