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首页> 外文期刊>Nature >Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios
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Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios

机译：早期的髓系谱系选择不是由随机的PU.1与GATA1蛋白质比率引发的

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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.
机译：造血谱系决定的基础机制仍存在争议。具有谱系重编程能力（3），正向自调控（4,5）和相互抑制（6,7）的谱系相关转录因子（1,2）被描述为在未定型细胞群体中表达（8）。 。这导致了这样的假设，即谱系选择是细胞内源性启动的，并由随机波动的交叉拮抗转录因子的随机转换决定（3）。但是，这个假设是根据快照和/或总体平均分析中的RNA表达数据开发的（9-12）。因此，不能排除谱系选择的替代模型。在这里，我们使用新型的报告基因小鼠系和实时成像技术对转录因子GATA1和PU.1（也称为SPI1）进行连续单细胞长期定量分析。我们分析整个造血干细胞分化成巨核细胞-类红细胞和粒细胞-单核细胞谱系。观察到的表达动力学与以下假设不相容：PU.1和GATA1之间的随机切换先于并启动了巨核细胞-红系与粒细胞-单核细胞谱系的决策。相反，我们的发现表明，这些转录因子仅在执行和加强谱系选择后才起作用。这些结果挑战了当前流行的早期髓系谱系选择模型。

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  • 来源
    《Nature》 |2016年第7611期|299-302|共4页
  • 作者

    Hoppe Philipp S.; Schwarzfischer Michael; Loeffler Dirk; Kokkaliaris Konstantinos D.; Hilsenbeck Oliver; Moritz Nadine; Endele Max; Filipczyk Adam; Gambardella Adriana; Ahmed Nouraiz; Etzrodt Martin; Coutu Daniel L.; Rieger Michael A.; Marr Carsten; Strasser Michael K.; Schauberger Bernhard; Burtscher Ingo; Ermakova Olga; Burger Antje; Lickert Heiko; Nerlov Claus; Theis Fabian J.; Schroeder Timm;

  • 作者单位

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland|Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Inst Computat Biol, D-85764 Neuherberg, Germany;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland|Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland|Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland|Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany|Helmholtz Zentrum Munchen, Inst Computat Biol, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland|Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland;

    Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Inst Computat Biol, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Inst Computat Biol, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, Inst Stem Cell Res, Business Campus Garching, D-85748 Garching, Germany;

    CNR, Ist Biol Cellulare & Neurobiol, I-00015 Monterotondo, Italy;

    Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany;

    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, Inst Stem Cell Res, Business Campus Garching, D-85748 Garching, Germany|Tech Univ Munich, Fac Med, Beta Cell Biol, D-80333 Munich, Germany;

    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England|EMBL Mouse Biol Unit, I-00015 Monterotondo, Italy;

    Helmholtz Zentrum Munchen, Inst Computat Biol, D-85764 Neuherberg, Germany|Tech Univ Munich, Dept Math, D-85748 Garching, Germany;

    ETH, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland|Helmholtz Zentrum Munchen, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany;

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