Multimodal measurements of single-cell profiles are proving increasingly useful for characterizing cell states and regulatory mechanisms. In the present study, we developed PHAGE-ATAC (Assay for Transposase-Accessible Chromatin), a massively parallel droplet-based method that uses phage displaying, engineered, camelid single-domain antibodies (‘nanobodies’) for simultaneous single-cell measurements of protein levels and chromatin accessibility profiles, and mitochondrial DNA-based clonal tracing. We use PHAGE-ATAC for multimodal analysis in primary human immune cells, sample multiplexing, intracellular protein analysis and the detection of SARS-CoV-2 spike protein in human cell populations. Finally, we construct a synthetic high-complexity phage library for selection of antigen-specific nanobodies that bind cells of particular molecular profiles, opening an avenue for protein detection, cell characterization and screening with single-cell genomics.

事实证明，单细胞概况的多模态测量对于表征细胞状态和调节机制越来越有用。在本研究中，我们开发了 PHAGE-ATAC（转座酶可及染色质测定），这是一种基于液滴的大规模并行方法，使用噬菌体展示、工程化、骆驼单域抗体（“纳米抗体”）同时进行单细胞测量蛋白质水平和染色质可及性概况，以及基于线粒体 DNA 的克隆追踪。我们使用 PHAGE-ATAC 对人类原代免疫细胞进行多模式分析、样本多重分析、细胞内蛋白质分析以及人类细胞群中 SARS-CoV-2 刺突蛋白的检测。最后，我们构建了一个合成的高复杂性噬菌体库，用于选择结合特定分子谱的细胞的抗原特异性纳米抗体，为蛋白质检测、细胞表征和单细胞基因组学筛选开辟了途径。