Department of Living Matter, AMOLF, Amsterdam, Netherlands.
Department of Cell Biology, Erasmus University Medical Centre, Rotterdam, Netherlands.
Elife. 2021 Dec 15;10:e66955. doi: 10.7554/eLife.66955.
Cell fate is maintained over long timescales, yet molecular fluctuations can lead to spontaneous loss of this differentiated state. Our simulations identified a possible mechanism that explains life-long maintenance of ASE neuron fate in by the terminal selector transcription factor CHE-1. Here, fluctuations in CHE-1 level are buffered by the reservoir of CHE-1 bound at its target promoters, which ensures continued expression by preferentially binding the promoter. We provide experimental evidence for this mechanism by showing that expression was resilient to induced transient CHE-1 depletion, while both expression of CHE-1 targets and ASE function were lost. We identified a 130 bp promoter fragment responsible for this resilience, with deletion of a homeodomain binding site in this fragment causing stochastic loss of ASE identity long after its determination. Because network architectures that support this mechanism are highly conserved in cell differentiation, it may explain stable cell fate maintenance in many systems.
细胞命运在长时间内得以维持，但分子波动可能导致其分化状态的自发丧失。我们的模拟确定了一种可能的机制，该机制解释了终末选择转录因子 CHE-1 如何在 中维持 ASE 神经元命运的终身维持。在这里，通过 CHE-1 结合其靶启动子的储库缓冲 CHE-1 水平的波动，这确保了通过优先结合 启动子来持续表达 。我们通过显示 表达对诱导的 CHE-1 瞬时耗竭具有弹性来为该机制提供实验证据，而 CHE-1 靶标和 ASE 功能的表达都丧失了。我们确定了一个负责这种弹性的 130bp 启动子片段，该片段中的同源域结合位点缺失会导致 ASE 身份在其确定后很长时间内随机丧失。因为支持这种机制的网络架构在细胞分化中高度保守，所以它可能解释了许多系统中稳定的细胞命运维持。
