Capicua is a fast-acting transcriptional brake.
Capicua is a fast-acting transcriptional brake.
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DOI：
10.1016/j.cub.2021.05.061
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发表时间：
2021-08-23
期刊：
影响因子：
--
通讯作者：
Shvartsman SY
中科院分区：
文献类型：
--
作者：
Patel AL;Zhang L;Keenan SE;Rushlow CA;Fradin C;Shvartsman SY
尽管转录抑制因子的分子分辨率不断提高，但对基因抑制的时间方面仍知之甚少。在这里，我们讨论由Capicua(CIC)转录抑制的动态，它是正常发育所必需的，在人类癌症和神经退行性疾病中通常发生突变。我们报道了基于活体成像和光遗传扰动的依赖于CIC的基因抑制在果蝇早期胚胎中的速度限制，CIC最初是在那里发现的。我们对CIC浓度和核内迁移率的测量，以及对CIC靶基因活性的实时监测，表明在移除光遗传去抑制信号后的几分钟内，转录抑制速度非常快。同时，对CIC靶基因转录爆发的定量分析支持一种抑制机制，该机制为猝发的产生提供了快速作用的刹车。这项工作对CIC基因调控的潜在机制设置了定量限制。Patel等人。报告果蝇早期胚胎中Capicua转录抑制的时间尺度。Capicua的生物物理性质是在间期核中测量的。优化的光开关MEK切换基因抑制。光遗传学扰动和新生转录产物的现场记者揭示了快速作用的基因抑制。
Even though transcriptional repressors are studied with ever-increasing molecular resolution, the temporal aspects of gene repression remain poorly understood. Here, we address the dynamics of transcriptional repression by Capicua (Cic), which is essential for normal development and is commonly mutated in human cancers and neurodegenerative diseases. We report the speed limit for Cic-dependent gene repression based on live imaging and optogenetic perturbations in the early Drosophila embryo, where Cic was originally discovered. Our measurements of Cic concentration and intranuclear mobility, along with real-time monitoring of the activity of Cic target genes, reveal remarkably fast transcriptional repression within minutes of removing an optogenetic de-repressive signal. In parallel, quantitative analyses of transcriptional bursting of Cic target genes support a repression mechanism providing a fast-acting brake on burst generation. This work sets quantitative constraints on potential mechanisms for gene regulation by Cic. Patel et al. report the timescale of transcriptional repression by Capicua in the early Drosophila embryo. Biophysical properties of Capicua are measured in interphase nuclei. Optimized photoswitchable MEK toggles gene repression. Optogenetic perturbations and live reporters of nascent transcript production reveal fast-acting gene repression.
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