German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg University, Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
German Cancer Research Center (DKFZ), Computational Genome Biology Group, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Cell Syst. 2018 Jan 24;6(1):52-64.e4. doi: 10.1016/j.cels.2017.10.015. Epub 2017 Nov 30.
Cellular signaling networks coordinate physiological processes in all multicellular organisms. Within networks, modules switch their function to control signaling activity in response to the cellular context. However, systematic approaches to map the interplay of such modules have been lacking. Here, we generated a context-dependent genetic interaction network of a metazoan's signaling pathway. Using Wnt signaling in Drosophila as a model, we measured >290,000 double perturbations of the pathway in a baseline state, after activation by Wnt ligand or after loss of the tumor suppressor APC. We found that genetic interactions within the Wnt network globally rewired after pathway activation. We derived between-state networks that showed how genes changed their function between state-specific networks. This related pathway inhibitors across states and identified genes required for pathway activation. For instance, we predicted and confirmed the ER-resident protein Catsup to be required for ligand-mediated Wnt signaling activation. Together, state-dependent and between-state genetic interaction networks identify responsive functional modules that control cellular pathways.
细胞信号网络协调所有多细胞生物的生理过程。在网络中，模块会切换其功能，以响应细胞环境来控制信号活性。然而，缺乏系统性的方法来绘制这种模块的相互作用图谱。在这里，我们生成了一个后生动物信号通路的依赖于上下文的遗传相互作用网络。我们以果蝇中的 Wnt 信号作为模型，在基线状态、Wnt 配体激活后或肿瘤抑制因子 APC 缺失后，测量了 >290000 次对该通路的双敲除扰动。我们发现，通路激活后，Wnt 网络中的遗传相互作用全局重连。我们推导出了状态间网络，显示了基因在特定状态网络之间如何改变其功能。这将通路抑制剂关联到不同状态，并确定了通路激活所需的基因。例如，我们预测并证实内质网驻留蛋白 Catsup 是配体介导的 Wnt 信号激活所必需的。总之，依赖于状态和状态间的遗传相互作用网络确定了控制细胞通路的响应性功能模块。
