Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
Dev Cell. 2015 Sep 14;34(5):592-607. doi: 10.1016/j.devcel.2015.07.014. Epub 2015 Aug 27.
Elucidating the mechanism of cell lineage differentiation is critical for our understanding of development and fate manipulation. Here we combined systematic perturbation and direct lineaging to map the regulatory landscape of lineage differentiation in early C. elegans embryogenesis. High-dimensional phenotypic analysis of 204 essential genes in 1,368 embryos revealed that cell lineage differentiation follows a canalized landscape with barriers shaped by lineage distance and genetic robustness. We assigned function to 201 genes in regulating lineage differentiation, including 175 switches of binary fate choices. We generated a multiscale model that connects gene networks and cells to the experimentally mapped landscape. Simulations showed that the landscape topology determines the propensity of differentiation and regulatory complexity. Furthermore, the model allowed us to identify the chromatin assembly complex CAF-1 as a context-specific repressor of Notch signaling. Our study presents a systematic survey of the regulatory landscape of lineage differentiation of a metazoan embryo.
阐明细胞谱系分化的机制对于我们理解发育和命运操纵至关重要。在这里，我们结合系统扰动和直接谱系追踪，绘制了早期秀丽隐杆线虫胚胎发生中谱系分化的调控景观图。对 1,368 个胚胎中的 204 个必需基因进行高维表型分析表明，细胞谱系分化遵循一个有规律的景观，其障碍由谱系距离和遗传鲁棒性塑造。我们将 201 个基因分配到调节谱系分化的功能中，包括 175 个二元命运选择的开关。我们生成了一个多尺度模型，将基因网络和细胞连接到实验映射的景观上。模拟表明，景观拓扑决定了分化的倾向和调控的复杂性。此外，该模型使我们能够识别染色质组装复合物 CAF-1 作为 Notch 信号的特定于上下文的抑制剂。我们的研究对后生动物胚胎谱系分化的调控景观进行了系统调查。
