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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

1
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
2
Research Unit Stem Cell Dynamics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
3
Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
4
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
5
Institute of Diabetes and Regeneration Research, Institute of Stem Cell Research, Helmholtz Zentrum München, Business Campus Garching, 85748 Garching, Germany.
6
Istituto di Biologia Cellulare e Neurobiologia, CNR, 00015 Monterotondo, Italy.
7
Institute of Developmental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
8
Beta Cell Biology, Medical Faculty, Technical University Munich (TUM), 80333 Munich, Germany.
9
EMBL Mouse Biology Unit, 00015 Monterotondo, Italy.
10
Department of Mathematics, Technical University Munich, 85748 Garching, Germany.

Abstract

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.

PMID:
27411635
DOI:
10.1038/nature18320
[Indexed for MEDLINE]

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