Grosselin, K. et al. Nat. Genet. 51, 1060–1066 (2019).

Rare cell types can have an outsized biological effect, but their sparsity makes them impossible to detect in bulk samples. To study the effect of such heterogeneity, Grosselin et al. developed a microfluidic device for single-cell chromatin immunoprecipitations. In one channel, cells are embedded in droplets, lysed and treated with MNase to fragment their chromatin; in another channel, barcoded beads are encapsulated. Following fusion of these two types of droplets, the nucleosomes in each cell are tagged with a specific barcode. After pooling and immunoprecipitation of activating and repressing histone marks, each modification can be traced back to its cell of origin. The authors probed hundreds of cells from drug-resistant and susceptible breast tumors, and found a resistance signature in a low percentage of drug-sensitive cells. At 4% of the overall population, this cell type was too sparse to be detected in a bulk sample, but it can provide important clues about the development of drug resistance during tumor progression.