Spatial joint profiling of DNA methylome and transcriptome in tissues

The spatial resolution of omics analyses is fundamental to understanding tissue biology^1-3. The capacity to spatially profile DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation^4,5, is lacking. Here we introduce a method for whole-genome spatial co-profiling of DNA methylation and the transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and the postnatal mouse brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The concordance and distinction in spatial patterns of the two modalities highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics that underlie mammalian embryogenesis for both the epigenome and transcriptome, revealing details of sequence-, cell-type- and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to include DNA cytosine methylation, enabling a more comprehensive understanding of tissue biology across development and disease.