Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios
Hoppe PS, Schwarzfischer M, Loeffler D, Kokkaliaris KD, Hilsenbeck O, Moritz N, Endele M, Filipczyk A, Gambardella A, Ahmed N, Etzrodt M, Coutu DL, Rieger MA, Marr C, Strasser MK, Schauberger B, Burtscher I, Ermakova O, Burger A, Lickert H, Nerlov C, Theis FJ, Schroeder T (2016)
Publication Type: Journal article
Publication year: 2016
Journal
Book Volume: 535
Pages Range: 299-302
Journal Issue: 7611
DOI: 10.1038/nature18320
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.
Involved external institutions
Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Switzerland (CH)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
University of Oxford
United Kingdom (GB)
Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy
Italy (IT)
Switzerland (CH)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
University of Oxford
United Kingdom (GB)
Consiglio Nazionale delle Ricerche (CNR) / National Research Council of Italy
Italy (IT)
How to cite
APA:
Hoppe, P.S., Schwarzfischer, M., Loeffler, D., Kokkaliaris, K.D., Hilsenbeck, O., Moritz, N.,... Schroeder, T. (2016). Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios. Nature, 535(7611), 299-302. https://doi.org/10.1038/nature18320
MLA:
Hoppe, Philipp S., et al. "Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios." Nature 535.7611 (2016): 299-302.
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