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

Article

关键词: TRANSCRIPTION FACTOR GATA-1;    HEMATOPOIETIC STEM-CELLS;    PROGENITOR CELLS;    ERYTHROID-DIFFERENTIATION;    MULTIPOTENT PROGENITORS;    TRANSGENIC MICE;    COMMITMENT;    SPECIFICATION;    ACTIVATION;    EXPRESSION;   

DOI  :  10.1038/nature18320

来源: SCIE

【 摘 要 】

The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors(1,2) with the capacity for lineage reprogramming(3), positive auto-regulation(4,5) and mutual inhibition(6,7) have been described as being expressed in uncommitted cell populations(8). This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors(3). However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses(9-12). 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.

【 授权许可】

Free