Massively multiplex chemical transcriptomics at single-cell resolution

The sci-Plex technique holds promise for cell biology research in cancer, infectious diseases, autoimmune disorders, prenatal medicine and many other medical and basic science areas. Results from proof-of-concept testing are reported today  in Science.

Most high-throughput , cell-response screening tools provide either a course readout, such as cell survival or proliferation,  or a highly specific finding,  such as a blocked enzyme.

sciPlex gives a more global view of what happens inside a variety of different cells when exposed to various agents.  The information could help in exploring, for example, the way a drug works, how cells become resistant to treatment, or why a therapy is effective for some people but not others. sciPlex might also be a helpful  tool in some new research fields,  such  as studies of synthetic embryos,  reprogrammed cells or organoids.

Cole Trapnell and Jay Shendure of the Department of Genome Sciences at the University of Washington School of Medicine and of the Brotman Baty Institute in Seattle oversaw the sci-Plex development, which was led by Sanjay  Srivatsan,  José L. McFaline-Figueroa, and Vinjay Ramani.

Source – University of Washington School of Medicine

High-throughput chemical screens typically use coarse assays such as cell survival, limiting what can be learned about mechanisms of action, off-target effects, and heterogeneous responses. Here, the developers 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, they applied sci-Plex to screen three cancer cell lines exposed to 188 compounds. In total, they profiled ~650,000 single-cell transcriptomes across ~5000 independent samples in one experiment. Their 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, these results with histone deacetylase inhibitors support the view that chromatin acts as an important reservoir of acetate in cancer cells.

Availability – https://github.com/cole-trapnell-lab/sci-plex