Spatial joint profiling of DNA methylome and transcriptome in tissues
- Nature. 2025 Oct;646(8087):1261-1271. doi: 10.1038/s41586-025-09478-x.
- 1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 2. Institute of RNA innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 3. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 4. Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- 5. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
- 6. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 7. Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
- 8. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 9. Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- 10. Institute of Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
- # Contributed equally.
The spatial resolution of omics analyses is fundamental to understanding tissue biology1-3. The capacity to spatially profile DNA methylation, which is a canonical epigenetic MARK extensively implicated in transcriptional regulation4,5, 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.