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Hoppe, P.S. ; Schwarzfischer, M. ; Loeffler, D. ; Kokkaliaris, K.D. ; Hilsenbeck, O. ; Moritz, N. ; Endele, M. ; Filipczyk, A. ; Gambardella, A.* ; Ahmed, N.* ; Etzrodt, M.* ; Coutu, D.L.* ; Rieger, M.A. ; Marr, C. ; Strasser, M. ; Schauberger, B. ; Burtscher, I. ; Ermakova, O.* ; Bürger, A. ; Lickert, H. ; Nerlov, C.* ; Theis, F.J. ; Schroeder, T.

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

Nature 535, 299-302 (2016)

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Open Access Green as soon as Postprint is submitted to ZB.

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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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