Cusanovich, D.A. et al. Science 348, 910–914 (2015).

The accessibility of chromatin to regulatory proteins provides an important layer of gene expression control, and it varies between tissues. Cusanovich et al. now establish genome-wide accessibility mapping in single cells and use combinatorial indexing to profile large numbers of cells. The researchers add barcode sequence–bearing transposase, which preferentially inserts into accessible regions, to uniquely label single permeabilized nuclei deposited in individual wells of 96-well plates. Nuclei are then pooled, redistributed into new wells and lysed, and their contents are amplified with a second barcode and sequenced. The method allows mixed human cell lines to be distinguished by their accessibility landscapes. By pooling nearly 15,000 cells from different experiments, the authors detected ∼96% of sites found by bulk-population DNase I hypersensitivity sequencing. The method can detect heterogeneity within a single cell type or distinguish different cell types on the basis of relatively shallow sequencing.