Saunders Reuben A, Allen William E, Pan Xingjie, Sandhu Jaspreet, Lu Jiaqi, Lau Thomas K, Smolyar Karina, Sullivan Zuri A, Dulac Catherine, Weissman Jonathan S, Zhuang Xiaowei
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Whitehead Institute, Cambridge, MA 02139, USA; University of California, San Francisco, San Francisco, CA 94158, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USA; Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, Cambridge, MA 02138, USA.
Cell. 2025 Jun 11. doi: 10.1016/j.cell.2025.05.022.
Metazoan life requires the coordinated activities of thousands of genes in spatially organized cell types. Understanding the basis of tissue function requires approaches to dissect the genetic control of diverse cellular and tissue phenotypes in vivo. Here, we present Perturb-Multimodal (Perturb-Multi), a paired imaging and sequencing method to construct large-scale, multimodal genotype-phenotype maps in tissues with pooled genetic perturbations. Using imaging, we identify perturbations in individual cells while simultaneously measuring their gene expression profiles and subcellular morphology. Using single-cell sequencing, we measure full transcriptomic responses to the same perturbations. We apply Perturb-Multi to study hundreds of genetic perturbations in the mouse liver. Our data suggest the genetic regulators and mechanisms underlying the dynamic control of hepatocyte zonation, the unfolded protein response, and steatosis. Perturb-Multi accelerates discoveries of the genetic basis of complex cell and tissue physiology and provides critical training data for emerging machine learning models of cellular function.
后生动物的生命需要数千个基因在空间组织的细胞类型中协同活动。理解组织功能的基础需要在体内剖析多种细胞和组织表型的遗传控制方法。在此，我们展示了扰动多模态（Perturb-Multi）方法，这是一种将成像与测序相结合的方法，用于在具有汇集遗传扰动的组织中构建大规模、多模态的基因型-表型图谱。通过成像，我们在识别单个细胞扰动的同时，测量它们的基因表达谱和亚细胞形态。通过单细胞测序，我们测量对相同扰动的完整转录组反应。我们应用Perturb-Multi方法研究小鼠肝脏中的数百种遗传扰动。我们的数据揭示了肝细胞区域化、未折叠蛋白反应和脂肪变性动态控制背后的遗传调节因子和机制。Perturb-Multi方法加速了对复杂细胞和组织生理学遗传基础的发现，并为新兴的细胞功能机器学习模型提供了关键的训练数据。
