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: The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors 1,2 with the capacity for lineage reprogramming 3, positive auto-regulation 4,5 and mutual inhibition 6,7 have been described as being expressed in uncommitted cell populations 8. This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors 3. However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses 9,10,11,12. 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.

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