Spatially-mapped single-cell chromatin accessibility

High-throughput single-cell epigenomic assays can resolve the heterogeneity of cell types and states in complex tissues, however, spatial orientation within the network of interconnected cells is lost. Here, we present a novel method for highly scalable, spatially resolved, single-cell profiling of chromatin states. We use high-density multiregional sampling to perform single-cell combinatorial indexing on Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin (sciMAP-ATAC) to produce single-cell data of an equivalent quality to non-spatially resolved single-cell ATAC-seq, where each cell is localized to a three-dimensional position within the tissue. A typical experiment comprises between 96 and 384 spatially mapped tissue positions, each producing 10s to over 100 individual single-cell ATAC-seq profiles, and a typical resolution of 214 cubic microns; with the ability to tune the resolution and cell throughput to suit each target application. We apply sciMAP-ATAC to the adult mouse primary somatosensory cortex, where we profile cortical lamination and demonstrate the ability to analyze data from a single tissue position or compare a single cell type in adjacent positions. We also profile the human primary visual cortex, where we produce spatial trajectories through the cortex. Finally, we characterize the spatially progressive nature of cerebral ischemic infarct in the mouse brain using a model of transient middle cerebral artery occlusion. We leverage the spatial information to identify novel and known transcription factor activities that vary by proximity to the ischemic infarction core with cell type specificity.