美国华盛顿大学Cole Trapnell、Jay Shendure等研究人员合作开发了能够实现细胞分辨率水平的大规模多路单化学转录组学技术。相关论文2019年12月5日在线发表于《科学》。

研究人员报道了sci-Plex，其使用“nuclear hashing”来量化对单细胞分辨率下数千个独立扰动的全局转录反应。作为概念验证，研究人员应用sci-Plex筛选了暴露于188种化合物的3种癌细胞系。在一个实验中，研究人员在约5000个独立样本中分析了约650000个单细胞转录组。研究结果表明，对特定化合物的反应具有实质性的细胞间异质性，对化合物家族的反应具有共同性，并深入了解了家族中的不同性质。此外，研究人员对HDAC抑制剂的研究结果支持了这样一种观点，即染色质在癌细胞中是乙酸盐的重要储存库。

据介绍，高通量化学筛选通常采用粗测定法，例如 细胞存活，限制了对作用机理、脱靶作用和异质反应的了解。

附：英文原文

Title: Massively multiplex chemical transcriptomics at single cell resolution

Author: Sanjay R Srivatsan, José L. McFaline-Figueroa, Vijay Ramani, Lauren Saunders, Junyue Cao, Jonathan Packer, Hannah A. Pliner, Dana L. Jackson, Riza M. Daza, Lena Christiansen, Fan Zhang, Frank Steemers, Jay Shendure, Cole Trapnell

Issue&Volume: 2019/12/05

Abstract: High-throughput chemical screens typically employ coarse assays, e.g. cell survival, limiting what can be learned about mechanisms of action, off-target effects, and heterogeneous responses. Here we introduce sci-Plex, which uses ‘nuclear hashing’ to quantify global transcriptional responses to thousands of independent perturbations at single-cell resolution. As a proof-of-concept, we applied sci-Plex to screen 3 cancer cell lines exposed to 188 compounds. In total, we profiled ~650,000 single-cell transcriptomes across ~5,000 independent samples in one experiment. Our results reveal substantial intercellular heterogeneity in response to specific compounds, commonalities in response to families of compounds, and insight into differential properties within families. In particular, our results with HDAC inhibitors support the view that chromatin acts as an important reservoir of acetate in cancer cells.

DOI: 10.1126/science.aax6234

Source: https://science.sciencemag.org/content/early/2019/12/04/science.aax6234