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The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors with the capacity for lineage reprogramming, positive auto-regulation and mutual inhibition have been described as being expressed in uncommitted cell populations. This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors. However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses. Alternative models of lineage choice therefore cannot be excluded. Here we use novel reporter mouse lines and live imaging for continuous single-cell long-term quantification of the transcription factors GATA1 and PU.1 (also known as SPI1). We analyse individual haematopoietic stem cells throughout differentiation into megakaryocytic-erythroid and granulocytic-monocytic lineages. The observed expression dynamics are incompatible with the assumption that stochastic switching between PU.1 and GATA1 precedes and initiates megakaryocytic-erythroid versus granulocytic-monocytic lineage decision-making. Rather, our findings suggest that these transcription factors are only executing and reinforcing lineage choice once made. These results challenge the current prevailing model of early myeloid lineage choice.

Original publication

DOI

10.1038/nature18320

Type

Journal article

Journal

Nature

Publication Date

13/07/2016

Volume

535

Pages

299 - 302

Keywords

Animals, Cell Differentiation, Cell Lineage, Erythrocytes, Feedback, Physiological, Female, GATA1 Transcription Factor, Genes, Reporter, Granulocytes, Hematopoiesis, Hematopoietic Stem Cells, Male, Megakaryocytes, Mice, Models, Biological, Monocytes, Myeloid Cells, Proto-Oncogene Proteins, Reproducibility of Results, Single-Cell Analysis, Stochastic Processes, Trans-Activators