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摘要 : 诱导细胞系的转录因子是怎样在造血细胞系中促进细胞命运的存在争议。

 诱导细胞系的转录因子是怎样在造血细胞系中促进细胞命运的存在争议。细胞群层面的分析已经发现了正向反馈和相互抑制的存在,这表明细胞系选择是被波动的对抗性转录因子随机驱动的。Timm Schroeder 及同事通过活体成像和单细胞分析显示,造血干细胞所做的关于是沿megakaryocytic–erythroid 细胞系还是沿granulocytic–monocytic细胞系分化的决定并不取决于在细胞系特异性转录因子PU.1 和GATA1之间的这种随机切换,这一结论向以前关于早期骨髓细胞系选择的模型提出了挑战。


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


The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors1, 2 with the capacity for lineage reprogramming3, positive auto-regulation4, 5and 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.

来源: Nature 浏览次数:1


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