Foo Sun Melody, Sun Yujia, Lim Bomyi, Ziukaite Ruta, O'Brien Kevin, Nien Chung-Yi, Kirov Nikolai, Shvartsman Stanislav Y, Rushlow Christine A
Department of Biology, New York University, New York, NY 10003, USA.
Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Curr Biol. 2014 Jun 16;24(12):1341-1346. doi: 10.1016/j.cub.2014.04.032. Epub 2014 Jun 5.
Zygotic genome activation (ZGA) is a major genome programming event whereby the cells of the embryo begin to adopt specified fates. Experiments in Drosophila and zebrafish have revealed that ZGA depends on transcription factors that provide large-scale control of gene expression by direct and specific binding to gene regulatory sequences. Zelda (Zld) plays such a role in the Drosophila embryo, where it has been shown to control the action of patterning signals; however, the mechanisms underlying this effect remain largely unclear. A recent model proposed that Zld binding sites act as quantitative regulators of the spatiotemporal expression of genes activated by Dorsal (Dl), the morphogen that patterns the dorsoventral axis. Here we tested this model experimentally, using enhancers of brinker (brk) and short gastrulation (sog), both of which are directly activated by Dl, but at different concentration thresholds. In agreement with the model, we show that there is a clear positive correlation between the number of Zld binding sites and the spatial domain of enhancer activity. Likewise, the timing of expression could be advanced or delayed. We present evidence that Zld facilitates binding of Dl to regulatory DNA, and that this is associated with increased chromatin accessibility. Importantly, the change in chromatin accessibility is strongly correlated with the change in Zld binding, but not Dl. We propose that the ability of genome activators to facilitate readout of transcriptional input is key to widespread transcriptional induction during ZGA.
合子基因组激活（ZGA）是一项重大的基因组编程事件，通过该事件胚胎细胞开始分化为特定的细胞命运。果蝇和斑马鱼实验表明，ZGA依赖于转录因子，这些转录因子通过直接和特异性结合基因调控序列来大规模控制基因表达。在果蝇胚胎中，Zelda（Zld）发挥着这样的作用，已证明它能控制模式信号的作用；然而，这种效应背后的机制在很大程度上仍不清楚。最近提出的一个模型认为，Zld结合位点作为由Dorsal（Dl）激活的基因时空表达的定量调节剂，Dl是一种沿背腹轴形成模式的形态发生素。在这里，我们使用brinker（brk）和短原肠胚形成（sog）的增强子对该模型进行了实验测试，这两个增强子均由Dl直接激活，但激活的浓度阈值不同。与该模型一致，我们表明Zld结合位点的数量与增强子活性的空间域之间存在明显的正相关。同样，表达时间可以提前或延迟。我们提供的证据表明，Zld促进Dl与调控DNA的结合，并且这与染色质可及性增加有关。重要的是，染色质可及性的变化与Zld结合的变化密切相关，而与Dl无关。我们提出，基因组激活剂促进转录输入读出的能力是ZGA期间广泛转录诱导的关键。
