Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios.
Dem Zellschicksal auf die Schliche kommen
Monitoring cell fates
||Prof. Dr. Dr. Fabian Theis||
The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors1, 2 with the capacity for lineage reprogramming3, positive auto-regulation4, 5 and mutual inhibition6, 7 have been described as being expressed in uncommitted cell populations8. This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors3. However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses9, 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.
Core statement Pressemitteilung:
An international team of researchers led by scientists of Helmholtz Zentrum München and ETH Zurich has been studying the factors influencing the development of different blood cells. Their research shows that certain molecular mechanisms are not as relevant as previously assumed. This finding helps to improve our understanding of diseases such as leukaemia and anaemia. The study is published in ‘Nature’.
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