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

Nature 535, 299-302 (2016)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Transcription Factor Gata-1; Hematopoietic Stem-cells; Progenitor Cells; Erythroid-differentiation; Multipotent Progenitors; Transgenic Mice; Commitment; Specification; Activation; Expression
Reviewing status