Epigenomic tomography for probing spatially defined chromatin state in the brain

Spatially resolved epigenomic profiling is critical for understanding biology in the mammalian brain. Single-cell spatial epigenomic assays were developed recently for this purpose, but they remain costly and labor intensive for examining brain tissues across substantial dimensions and surveying a collection of brain samples. Here, we demonstrate an approach, epigenomic tomography, that maps spatial epigenomes of mouse brain at the scale of centimeters. We individually profiled neuronal and glial fractions of mouse neocortex slices with 0.5 mm thickness. Tri-methylation of histone 3 at lysine 27 (H3K27me3) or acetylation of histone 3 at lysine 27 (H3K27ac) features across these slices were grouped into clusters based on their spatial variation patterns to form epigenomic brain maps. As a proof of principle, our approach reveals striking dynamics in the frontal cortex due to kainic-acid-induced seizure, linked with transmembrane ion transporters, exocytosis of synaptic vesicles, and secretion of neurotransmitters. Epigenomic tomography provides a powerful and cost-effective tool for characterizing brain disorders based on the spatial epigenome. [Display omitted] •Mapping the spatial epigenome of brain using dissection and a low-input assay•Using k-means clustering to group peaks based on their patterns of spatial variation•Creating dual epigenomic tomography to compare brain samples•Detecting variation in mouse frontal cortex due to seizure Recent progress on spatial epigenomic profiling has been centered around single-cell assays. They offer extremely high spatial resolution and generate important insights on the microenvironment and cell-cell communications. These assays are powerful for capturing spatial dynamics in mammalian brains. Despite their advantages, single-cell spatial epigenomic assays are costly and laborious. Comparison of brain samples using these single-cell datasets requires complicated bioinformatic pipelines that are prone to errors and artifacts. Here, we develop a simple and cost-effective approach, referred to as epigenomic tomography, to map spatial brain epigenomes using a low-input epigenomic assay. Liu et al. develop an approach, referred to as epigenomic tomography, to map the spatial epigenome of mouse brain at a span of 1 cm with a resolution of 0.5 mm. As a proof of principle, epigenomic tomography data reveal striking changes in the frontal cortex due to kainic-acid-induced seizure.