Spatially resolved epigenomic profiling of single cells in complex tissues

SUMMARY The recent development of spatial omics methods enables single-cell profiling of the transcriptome and the 3D genome organization in a spatially resolved manner. Expanding the repertoire of spatial omics tools, a spatial epigenomics method will accelerate our understanding of the spatial regulation of cell and tissue functions. Here, we report a method for spatially resolved profiling of epigenomes in single cells using in-situ tagmentation and transcription followed by highly multiplexed imaging. We profiled histone modifications marking active promoters and enhancers, H3K4me3 and H3K27ac, and generated high-resolution spatial atlas of hundreds of active promoters and putative enhancers in embryonic and adult mouse brains. Our results further revealed putative promoter-enhancer pairs and enhancer hubs regulating the expression of developmentally important genes. We envision this approach will be generally applicable to spatial profiling of epigenetic modifications and DNA-binding proteins, advancing our understanding of how gene expression is spatiotemporally regulated by the epigenome.