Single-cell chromatin accessibility reveals principles of regulatory variation

A single-cell method for probing genome-wide chromatin accessibility has been developed; the results provide insight into the relationship between cell-to-cell variation associated with specific trans-factors and cis-elements, as well insights into the relationship between chromatin accessibility and three-dimensional genome organization. Technological advances for interrogating single cells are allowing a more detailed understanding of cell-to-cell variation in gene expression. Here, William Greenleaf and colleagues describe a single-cell transposase-based method, termed single-cell ATAC-seq (scATAC-seq), for probing DNA accessibility genome-wide. They generate chromatin accessibility maps in several types of mammalian cells, and although analysis of cellular variation at individual regulatory elements is not yet feasible, they can assess variation in accessibility across sets of genomic features and find particular transcription factors associated with increased accessibility variation. Cell-to-cell variation is a universal feature of life that affects a wide range of biological phenomena, from developmental plasticity1,2 to tumour heterogeneity3. Although recent advances have improved our ability to document cellular phenotypic variation4,5,6,7,8, the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of mammalian DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells by assay for transposase-accessible chromatin using sequencing (ATAC-seq)9 integrated into a programmable microfluidics platform. Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provide insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type-specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signalling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome compartments10 de novo, linking single-cell accessibility variation to three-dimensional genome organization. Single-cell analysis of DNA accessibility provides new insight into cellular variation of the ‘regulome’.