Department of Bioengineering, University of Washington, Seattle, United States.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Elife. 2018 Nov 20;7:e37851. doi: 10.7554/eLife.37851.
Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by -epigenetic mechanisms at individual gene loci. Here, we studied the activation of , which controls T-cell fate commitment. To disentangle and effects, we generated mice where two copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent -acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic -acting events on individual loci.
细胞命运决定是通过命运指定基因的开关式、不可逆激活来发生的。这些激活事件通常被认为与上游转录因子的变化紧密相关，但也可能受到单个基因座上的 -表观遗传机制的限制。在这里，我们研究了控制 T 细胞命运决定的 的激活。为了区分 和 效应，我们生成了带有可区分荧光蛋白标记的两个 拷贝的小鼠。对这些小鼠的祖细胞进行定量活细胞显微镜观察显示， 在随机延迟后平均多天后开启，这种延迟不仅在细胞之间变化，而且在同一细胞内的 等位基因之间也变化。遗传干扰以及数学建模表明，远端增强子控制着表观遗传激活的速度，而平行的 Notch 依赖性 作用步骤则从激活的基因座刺激表达。这些结果表明，发育命运转变可以通过单个基因座上的随机作用事件来控制。
