A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment.
A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment.
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DOI：
10.7554/elife.37851
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发表时间：
2018-11-20
期刊：
影响因子：
7.7
通讯作者：
Kueh HY
中科院分区：
文献类型：
--
作者：
Ng KK;Yui MA;Mehta A;Siu S;Irwin B;Pease S;Hirose S;Elowitz MB;Rothenberg EV;Kueh HY
细胞命运的决定是通过命运指定基因的开关一样的、不可逆的激活来发生的。这些激活事件通常被认为与上游转录因子的变化紧密耦合，但也可能受到单个基因位点的顺式表观遗传机制的限制。在这里，我们研究了控制t细胞命运承诺的Bcl11b的激活。为了区分顺式和反式效应，我们用可区分的荧光蛋白标记了两个Bcl11b拷贝的小鼠。从这些小鼠的祖细胞中定量活显微镜发现，Bcl11b在平均多天的随机延迟后开启，这不仅在细胞之间，而且在同一细胞内的Bcl11b等位基因之间也存在差异。遗传扰动和数学模型表明，远端增强子控制表观遗传激活的速率，而平行的notch依赖反式作用步骤刺激激活位点的表达。这些结果表明，发育命运的转变可以由单个基因座上的随机顺式作用事件控制。
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 cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b 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 trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.