Science 367, 45–51 (2019)

Transcriptomic profiling of single cells treated with small molecules mitigates cell–cell variability in cellular responses, but existing single-cell transcriptome sequencing (scRNA-seq) methods remain costly. The use of cellular barcoding with antibodies or lipid-modified oligonucleotides enables distinction of cells from different samples, but issues with scalability remain. Srivatsan et al. developed sci-Plex, which uses polyadenylated ssDNA oligonucleotides to barcode nuclei before pooling and scRNA-seq. From a single experiment with three cancer cell lines exposed to 188 compounds, the authors identified consistent transcriptional responses for particular HDAC inhibitors with alterations in genes involved in cell cycle arrest and cellular metabolism, such as enzymes for acetyl-CoA and citrate production. The authors found that the combination of HDAC inhibition and supplemented acetyl-CoA precursors reduced the extent of HDAC inhibitor-mediated transcriptional changes, while treatment with inhibitors of acetyl-CoA generation enhanced the changes. Overall, sci-Plex offers the ability to detect small-molecule-induced transcriptomic changes in single cells with high resolution.