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Nature. 2016 Jul 14;535(7611):299-302. doi: 10.1038/nature18320.

Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios.

Author information

Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
Research Unit Stem Cell Dynamics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Institute of Diabetes and Regeneration Research, Institute of Stem Cell Research, Helmholtz Zentrum München, Business Campus Garching, 85748 Garching, Germany.
Istituto di Biologia Cellulare e Neurobiologia, CNR, 00015 Monterotondo, Italy.
Institute of Developmental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Beta Cell Biology, Medical Faculty, Technical University Munich (TUM), 80333 Munich, Germany.
EMBL Mouse Biology Unit, 00015 Monterotondo, Italy.
Department of Mathematics, Technical University Munich, 85748 Garching, Germany.


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.

[Indexed for MEDLINE]

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